Preparation of quinoline-substituted carbonate and carbamate derivatives

ABSTRACT

The invention relates to a process for preparing quinoline-substituted carbonate and carbamate compounds, which are important intermediates in the synthesis of 6-O-substituted macrolide antibiotics. The process employs metal-catalyzed coupling reactions to provide a carbonate or carbamate of formula (I) or (II) or a substrate that can be reduced to obtain the same.

[0001] This application claims priority from the U.S. ProvisionalApplication Ser. No. 60/141,042, filed on Jun. 24, 1999.

TECHNICAL FIELD OF THE INVENTION

[0002] The present invention relates to the preparation ofquinoline-substituted carbonate and carbamate derivatives, which provideimportant intermediates in the synthesis of 6-O-substituted macrolideantibiotics. In one aspect, the invention relates to the processes forpreparing quinolyl-substituted carbonate or carbamate compounds andprocesses for preparing the compounds via an alkenol derivative. Inanother aspect, the invention relates to preparing carbonate orcarbamate compounds via a quinoline carboxaldehyde or a derivativethereof.

BACKGROUND OF THE INVENTION

[0003] 6-O-Methylerythromycin A (clarithromycin) is a potent macrolideantibiotic disclosed in U.S. Pat. No. 4,331,803.

[0004] The process for making clarithromycin, in general, can be thoughtof as a four-step procedure beginning with erythromycin A as thestarting material:

[0005] Step 1: optionally convert the 9-oxo group to an oxime;

[0006] Step 2: protect the 2′ and 4″ hydroxyl groups;

[0007] Step 3: methylate the 6-hydroxyl group; and

[0008] Step 4: deprotect at the 2′, 4″ and 9-positions.

[0009] Since the discovery of clarithromycin, new macrolide antibioticcompounds have been discovered and are disclosed in commonly-owned U.S.Pat. No. 5,886,549, filed Jul. 3, 1997. The compounds generally areprepared by known processes. However, the substitution at the 6-positionwith substituents other than the methyl group is not easy to accomplishand is accompanied by side reactions, by-products and low yields.

[0010] Recent developments provide more efficient and cleaner synthesesfor alkylating the 6-hydroxyl group. Novel processes allow substituentsother than the methyl in the 6-position of the erythromycin derivatives.Commonly-owned U.S. application Ser. No. 60/149,968, filed on Jun. 24,1999, discloses a process for preparing 6-O-substituted erythromycinderivatives and for preparing 6-O-substituted erythromycin ketolidesinvolving a palladium catalyzed process using carbonate or carbamatederivatives.

[0011] Preparation of the carbonate and carbamate derivatives involveuse of a variety of quinoline substituted intermediates. In Chem. Pharm.Bull., 1979, 27(1), 270-273, synthesis of 3-(3-quinolyl)-2-propyn-1-olis described. However, there are no known reports of quinolinesubstituted carbonate or carbamate derivatives or the methods ofpreparing them.

SUMMARY OF THE INVENTION

[0012] Various methods are disclosed for preparing quinoline-substitutedintermediates from which a carbonate, preferably t-butyl carbonate orcarbamate compound, is obtained. Processes described and claimed hereinemploy alcohols, esters, acetals, aldehydes, and carboxylic acids assuitable intermediate compounds. The intermediate compounds provide asuitable substrate from which a quinoline-substituted alkenol isobtained or the intermediate is directly hydrogenated to obtaincarbonate or carbamate derivatives of the invention.

[0013] In one aspect, the invention relates to a process of preparing acompound of the formula:

R¹—CH═CHCH₂OC(O)—X—R²  (I),

[0014] wherein R¹ is independently selected from hydrogen and quinolyloptionally substituted with one or more of:

[0015] (i) alkyl,

[0016] (ii) alkoxy,

[0017] (iii) aryl,

[0018] (iv) nitro, and

[0019] (v) halo;

[0020] R² is C₁-C₁₀-alkyl; X is —O— or —NR³; and R³ is hydrogen,C₁-C₆-alkyl or aryl, or R² and R³ taken together form an aromatic ornon-aromatic ring. The process comprises the steps of:

[0021] (a) preparing an intermediate selected from the group consistingof:

[0022] (i) R¹—C≡CCH₂OR⁴, wherein R⁴ is hydrogen or a hydroxy protectinggroup;

[0023] (ii) R¹—CH═CHC(O)OR⁵, wherein R⁵ is C₁ to C₆ lower alkyl;

[0024] (iii) R¹—CH═CHCH(OR⁶)(OR⁷), wherein R⁶ and R⁷ are independentlyC₁ to C₆ lower alkyl;

[0025] (iv) R¹—CH═CHC(O)OH;

[0026] (v) R¹—CH═CHCHO;

[0027] (vi) R¹—C≡C—CH₂—OC(O)—X—R²; and

[0028] (b) reducing or deprotecting an intermediate obtained in step(a); and

[0029] (c) optionally coupling the compound obtained from step (b) withan acylating reagent.

[0030] Intermediates (i) through (v) can be reduced to provide thealkenol derivative. The alkenol undergoes a coupling reaction with anacylating reagent, for example acyl halides, acid anhydrides, carbamoylhalides, and acid derivatives of aromatic and non-aromatic heterocycles,to afford compounds of formula (I). Intermediate (vi) can be directlyhydrogenated to provide compound (I).

[0031] Therefore, one process for preparing a compound of formula (I)via the alkenol generally comprises:

[0032] (a) preparing a compound of the formula R¹—CH═CHCH₂OR⁴, whereinR¹ and R⁴ are as previously defined;

[0033] (b) optionally deprotecting the compound obtained in step (a);and

[0034] (c) reacting the compound of the formula R¹—CH═CHCH₂OH with anacylating agent.

[0035] An alternative process for preparing the compound of formula (I)comprises:

[0036] (a) preparing a compound of the formula R¹—C≡C—CH₂—OC(O)—X—R²,wherein R¹ and R² are as previously defined; and

[0037] (b) hydrogenating the compound obtained in step (a).

[0038] In another aspect, the invention relates to a process ofpreparing a compound of the formula:

[0039] wherein

[0040] R¹, R² and X are as previously defined, and R⁸ is selected fromthe group consisting of:

[0041] (i) —CH═CH—R¹¹; wherein R¹¹ is hydrogen or alkyl; and

[0042] (ii) —C≡CR¹¹.

[0043] The process comprises the steps of:

[0044] (a) reacting a compound of the formula:

[0045] wherein X¹ is a halide, with an organometallic compound of theformula R⁸—M or R⁸—M—X¹, wherein R ⁸and X¹ are as defined above and M ismetal, and an acylating reagent;

[0046] (b) optionally hydrogenating the compound obtained in step (a),wherein R⁸ is alkynyl or substituted alkynyl, to afford thecorresponding compound wherein R⁸ is alkenyl or substituted alkenyl.

[0047] Yet another aspect of the invention relates to preparing acompound of formula (I) or (II) as defined above.

[0048] In yet another aspect, the invention relates to the compoundsselected from:

[0049] (a) R¹—CH═CHC(O)OR⁵;

[0050] (b) R¹—CH═CHCH(OR⁶)(OR⁷);

[0051] (c) R¹—CH═CHC(O)OH;

[0052] (d) R¹—CH═CHCHO;

[0053] (e) R¹—C≡C—CH₂—OC(O)—X—R²; and

[0054] (f) R¹—CH═CHCH₂OH;

[0055] wherein R¹, R², R⁵, R⁶ and R⁷ are as previously defined.

[0056] Processes of the invention provide carbonate or carbamatecompounds useful as intermediates in the synthesis of erythromycinderivatives, for example, macrolide antibiotics and erythromycinketolide compounds. Compounds of formula (I) or (II) are suitable forpreparing 6-O-substituted erythromycin derivatives having a6-O-quinolyl-substituted propenyl substituent.

DETAILED DESCRIPTION OF THE INVENTION

[0057] A number of terms are used herein to designate particularelements of the present invention. When so used, the following meaningsare intended:

[0058] The term “lower alkyl” or “alkyl” as used herein refers tostraight or branched chain saturated hydrocarbon radicals. “C_(x) toC_(y) alkyl” and “C_(x)-C_(y)”, wherein x and y are each an integer from1 to 20, denotes an alkyl group containing the number of carbons asdesignated by x and y, for example, the term “C₁ to C₆ alkyl” refers toa straight or branched chain saturated hydrocarbon radical containingfrom 1 to 6 carbon atoms. Exemplary lower alkyl or alkyl groups include,but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, t-butyl, pentyl, hexyl, and the like.

[0059] The term “alkenyl” as used herein refers to straight- orbranched-chain hydrocarbon radicals containing between two and sixcarbon atoms and possessing at least one carbon-carbon double bond.Examples of alkenyl radicals include vinyl, allyl, 2- or 3- butenyl, 2-,3- or 4-pentenyl, 2-, 3-, 4-, or 5-hexenyl, and the like, and isomericforms thereof.

[0060] The term “alkynyl” as used herein refers to straight orbranched-chain hydrocarbon radicals containing between two and sixcarbon atoms and possessing at least one carbon-carbon triple bond.Examples of alkynyl radicals include ethynyl, propargyl, propylidyne,and the like, and isomeric forms thereof.

[0061] The term “polar aprotic solvent” refers to polar organic solventslacking an easily removed proton including, but not limited to,N,N-dimethylformamide, N,N-dimethyl acetamide, N-methyl-2-pyrrolidone,hexamethylphosphoric triamide, tetrahydrofuran, 1,2-dimethoxyethane,acetonitrile, ethyl acetate, and the like, or a mixture thereof.

[0062] The term “acylating reagent” refers to a substituent capable ofplacing an acyl group or carbamoyl group onto a nucleophilic siteincluding, but not limited to, acyl halides, acid anhydrides, carbamoylhalides, acid derivatives of aromatic and non-aromatic heterocycles, andthe like. Exemplary acylating reagents include, but are not limited to,di-tert-butyl dicarbonate, di-isopropyl dicarbonate, t-butylchloroformate (not commercially available),2-(t-butoxycarbonyl-oxyimino)-2-phenylacetonitrile,N-t-butoxy-carbonyloxysuccinimide, 1-(t-butoxycarbonyl)-imidazole,dicyclohexylcarbamoyl chloride, diphenylcarbamoyl chloride, diisopropylcarbamoyl chloride, morpholine acid chloride, carbonyl diimidazole, andthe like.

[0063] Commonly owned, U.S. application Ser. No. 60/140,968, filed onJun. 24, 1999, describes a method for preparing 6-O-substitutedmacrolide derivatives which relates to the coupling of substituted orunsubstituted allyl carbonate or carbamate derivatives with a macrolidecore, and particularly a ketolide core. The method exemplifies onemethod of a number of syntheses available introducing substituted orunsubstituted allyl carbonate and carbamate substituents onto a parentcompound core.

[0064] Numerous processes for preparing the intermediates and thecorresponding carbonate or carbamate compounds therefrom are describedherein. Exemplary processes follow in Schemes 1-7, which are intended toillustrate a process of the invention and are not meant to limit thescope of the invention in any way. Isomeric forms of compounds describedin the Schemes are contemplated and considered as encompassed within thescope of the claimed invention. Various changes and modifications to thedisclosed embodiments will be apparent to those skilled in the art. Suchchanges and modifications are within the purview of the invention andcan be made without departing from the spirit and scope thereof.

[0065] One manner of preparing the alkenol intermediate involvescoupling a propargyl alcohol with a haloquinoline, and reducing thecompound obtained therefrom to the corresponding alkenol as exemplifiedin Scheme 1, below.

[0066] According to Scheme 1, a commercially available haloquinoline (1)wherein X¹ is bromine, chlorine, or iodine, is reacted with substitutedor unsubstituted propargyl alcohol in the presence of a base and apalladium-based catalyst. The reaction is carried out at a temperaturefrom 20° C. to 100° C. Preferably, the temperature is from about 25° C.to about 90° C.

[0067] The propargyl alcohol is either unsubstituted or substituted witha hydroxy protecting group R⁴. The protecting group can be one of manycommonly available hydroxy protecting groups. Typical hydroxy protectinggroups for R⁴ include, but are not limited to, tetrahydropyranyl,benzyl, trimethylsilyl, triisopropylsilyl, t-butyldimethylsilyl,t-butyldiphenylsilyl, formyl, acetyl, pivalyl, mesyl, and tosyl. Athorough discussion of protecting groups and the solvents in which theyare most effective is provided by T. W. Greene and P. G. M. Wuts inProtective Groups in Organic Synthesis, 3rd ed., John Wiley & Son, Inc.,1999.

[0068] At least one carbon of the quinoline-based starting material issubstituted with a halide selected from the group consisting of bromine,chlorine, and iodine, for example, bromoquinoline, chloroquinoline, andiodoquinoline. The haloquinoline is optionally substituted withaliphatic or aromatic substituents as well as nitrogen-containingmoieties including, but not limited to, alkyl, alkoxy, aryl, and nitro.

[0069] The catalyst used is either the 0-valent palladium species or itis generated in-situ, such as palladiumtriphenyl phosphine, by themethods known in the art. See for example, Beller et al. Angew. Chem.Int. Ed. Engl., 1995, 34(17), 1848. The palladium catalyst can beselected from the group consisting of palladium acetate,tetrakis(triphenylphosphine)-palladium, andtris(dibenzylideneacetate)dipalladium.

[0070] Treatment with palladium acetate or palladium on carbon proceedsin a facile manner when used with a promoter, preferably a phosphine. Asuitable phosphine is selected from triphenylphosphine,bis(diphenylphosphine)methane, bis(diphenylphosphine)ethane,bis(diphenylphosphine)propane, 1,4-bis(diphenylphosphine)butane,bis(diphenylphosphine)-pentane, tri(o-tolyl)phosphine, and the like. Theratio of palladium catalyst to the phosphine generally ranges from 1:1to about 1:8.

[0071] A halide, such as a copper halide or phase transfer catalyst,such as a tetrabutylammonium halide or tetrabutylammonium hydrogensulfate, can be used with the palladium-based catalysts to enhance thecoupling reation. The preferred copper halides are copper bromide andcopper iodide. Preferably, the phase transfer catalyst istetrabutylammonium bromide.

[0072] Useful bases for the invention are organic or inorganic bases.Exemplary inorganic bases include, but are not limited to, sodiumhydroxide, potassium hydroxide, ammonium hydroxide, sodium carbonate,potassium carbonate, ammonium carbonate, and the like, or a mixturethereof. Organic bases include, but are not limited to,dimethylaminopyridine, pyridine, dimethylamine, diethylamine,diisopropylamine, diisopropylethylamine, triethylamine, piperidine,pyrrolidine, pyrrole, triisopropylamine, and the like, or a mixturethereof.

[0073] The reaction can be carried out in an aprotic solvent. Typicalaprotic solvents are selected from N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone,hexamethylphosphoric triamide, tetrahydrofuran, 1,2-dimethoxyethane,methyl-t-butyl ether, toluene, heptane, acetonitrile and ethyl acetate.The preferred solvent is acetonitrile and N,N-dimethylformamide.

[0074] Exemplary conditions in which the reaction is carried out aredescribed below in Table 1. TABLE 1 Alcohol Amine Catalyst/PromoterTemp. Solvent Propargyl Et₃N Pd(PPh₃)₂Cl₂ 90° C. CuI, Et₃N alcohol(iPr)₂NH Pd(PPh₃)₂Cl₂ 75° C. CuI, EtOAc piperidine, nBu₄NBr Pd(OAc)₂,PPh₃ 45° C. CH₃CN, K₂CO₃, CuBr 10% Pd/C, PPh₃ 75° C. CH₃CN, piperidine,nBu₄NBr 5% Pd/C, PPh₃ 50° C. CH₃CN,

[0075] Conditions described above in Table 1 are meant to beillustrative and are not intended to limit the scope of the invention inany way.

[0076] The alkynol (2) obtained from the coupling reaction can bereduced to provide an alkenol (3). The alkynol (2) can be reduced eitherby catalytic semi-hydrogenation or reduction with an aluminumhydride-type reagent, which respectively produce the cis and the transisomers of an alkenol intermediate, as illustrated below.

[0077] In Scheme 2, the cis isomer (3-cis) of the alkenol can beprepared by catalytic semi-hydrogenation using hydrogen gas or bycatalytic transfer hydrogenation using a hydrogen donor source, such asammonium formate, formic acid, benzyltriethylammonium formate,hydrazine, cyclohexadiene, and the like, or a mixture thereof. Bothmethods employ a metal catalyst, such as palladium, platinum, or nickel.Typical catalysts for the semi-hydrogenation include, but are notlimited to, bis-dichloro triphenylphosphine palladium(II), palladiumacetate, tetrakis(triphenylphosphine)palladium,tris(dibenzylideneacetone)dipalladium, palladium on carbon, palladium oncalcium carbonate, palladium on barium sulfate, Raney Nickel, andplatinum black oxide.

[0078] Certain additives are suitable for the catalyticsemi-hydrogenation and can afford the cis isomer with improved yields.One suitable additive is 3,6-dithia-1,8-octanediol, however, variousother additives can be used in the hydrogenation.

[0079] Reacting the alkynol with an aluminum hydride type reagentsaffords the trans isomer (3-trans). Typically, the reaction is carriedout from −20° C. to 25° C. Aluminum hydride type reagent suitable forthe reaction are, for example, lithium aluminum hydride,diisobutylaluminum hydride, or Red-Al (sodiumbis(2-methoxyethoxy)aluminum hydride in toluene). About 1 to about 2molar equivalents of the aluminum hydride are reacted with oneequivalent of the 3-(3-quinolyl)-2-propyn-1-ol starting material.

[0080] Suitable reaction medium for the aluminum hydride-type reductionis anhydrous tetrahydrofuran. The reaction can also be carried out inpolar aprotic solvents, such as dimethoxyethane or methyl-t-butyl ether,and nonpolar aprotic solvents, such as toluene.

[0081] When R⁴ of the alkenol is a hydroxy protecting group, thecompound is deprotected prior to converting the alcohol to a carbonateor carbamate moiety. Deprotection of the hydroxy group can beaccomplished under acidic or basic conditions depending on the nature ofthe protecting group by standard methods known in the art. A summary ofthe procedures suitable for deprotecting the hydroxy group is describedin T. W. Greene and P. G. M. Wuts in Protective Groups in OrganicSynthesis, 2nd ed., John Wiley & Son, Inc., 1991, which is hereinincorporated by reference.

[0082] Conversion of alkenol (3) to the carbonate or carbamatederivatives can be carried out with a wide variety of reagents. Theproduct mixture obtained maintains the approximate proportions of cis totrans isomers which indicates the conversion preserves the orientationat the regiocenter as shown below.

[0083] According to Scheme 3, an acylating reagent is reacted with aquinoline-substituted alkenol (3-cis or 3-trans) obtained from thereduction reaction to convert the alcohol to a desired carbonate orcarbamate derivative of formula (I), the cis and trans isomers of whichcorrespond to compounds (4-cis) and (4-trans), wherein X is —O— and R²is C₁-C₁₀-alkyl, respectively. The reaction is carried out in an aproticsolvent at temperatures from about −30° C. to 50° C. Introducing eitheran organic or an inorganic base facilitates the reaction.

[0084] The acylating reagent places group of the formula

[0085] wherein X and R² are as previously defined, onto the oxygen atomof the hydroxy moiety. Acylating reagents suitable for preparing thecarbonate derivatives are typically acyl halides and acid anhydrides,which include, but are not limited to, di-tert-butyl dicarbonate anddi-isopropyl dicarbonate. Other exemplary reagents include are t-butylchloroformate, 2-(t-butoxy-carbonyloxyimino)-2-phenylacetonitrile,N-t-butoxycarbonyloxy-succinimide, and 1-(t-butoxy-carbonyl)imidazole,and the like. For preparing the preferred carbonate,3-(3-quinolyl)-2-propen-1-ol t-butyl carbonate the3-(3-quinolyl)-2-propen-1-ol intermediate is preferably treated withdi-tert-butyl dicarbonate.

[0086] Carbamate derivatives of formula (I) can be prepared by reactingthe alkenol, with a suitable carbamoyl chloride or the acid chloride ofan aromatic or non-aromatic nitrogen heterocycle in the presence ofbase. Exemplary acylating reagents for preparing the carbamate compoundsare selected from carbamoyl halides and acid derivatives of aromatic andnon-aromatic nitrogen containing heterocycles, including but not limitedto, dicyclohexylcarbamoyl chloride, diphenylcarbamoyl chloride,diisopropyl carbamoyl chloride, morpholine acid chloride, carbonyldiimidazole, and the like.

[0087] Aprotic solvents are selected from the group as described above.The preferred solvent is toluene. Dichloromethane is also suitable forthe reaction. Conversion of the alkenol proceeds in a more facile mannerwhen from about 0.01 to about 0.05 molar equivalents of a phase transferreagent relative to the alkenol starting material is added to thereaction mixture. A wide variety of phase transfer reagents are suitablefor the reaction including, but not limited to, n-tetrabutylammoniumhalides and n-tetrabutylammonium hydrogen sulfate. The preferred phasetransfer reagent is n-tetrabutylammonium hydrogen sulfate.

[0088] Alternatively, the alkynol (2) is coupled with the acylatingreagent to afford a carbonate or carbamate intermediate of the formulaR¹—C≡C—CH₂—OC(O)—X—R², wherein R¹ and R² are previously defined, whichcan be reduced to provide the alkenyl carbonate or carbamate compoundsof formula (I). The intermediate can be reduced by way of catalyticsemi-hydrogenation to provide the derivative of formula (I). Preferably,the intermediate is reduced using 5% palladium on calcium carbonatepoisoned with lead (Lindlar's catalyst, Pd/CaCO₃/Pb) and hydrogen gas,which provides the cis isomer (3-cis). The portion of Lindlar's catalystreacted with one equivalent of the alkynol starting material is fromabout 0.005 to about 0.2 weight/weight equivalents.

[0089] One alternate method of preparing the carbonate relates totreating a haloquinoline with propargyl alcohol, a copper halide, ormore preferably copper iodide, anddichlorobis-(triphenylphosphine)palladium(II) in the presence oftriethylamine in an aprotic solvent. The alkynol obtained therefrom isreduced by methods of hydrogenation or Red-Al reduction to afford analkenol, which can be coupled with an acylating agent to provide adesired derivative.

[0090] Another preferred method of preparing the alkynol involvesreacting a haloquinoline with propargyl alcohol, tetrabutylammoniumbromide, and palladium acetate or palladium on carbon in combinationwith a phosphine. The reaction is accomplished in the presence of asecondary amine, such as piperidine, or acetonitrile or mixtures of THFand water. Reduction of the alkynol with Red-Al is accomplished withtetrahydrofuran solvent and the resulting alkenol is coupled with anacylating reagent, such as di-tert-butyl dicarbonate, in the presence ofbase and tetrabutylammonium hydrogen sulfate in dichloromethane ortoluene.

[0091] Preferably, the haloquinoline starting material is selected from3-bromoquinoline or 3-iodoquinoline. The most preferred haloquinoline is3-bromoquinoline.

[0092] Other possible methods for preparing the alkenol involve usingacrolein acetal or vinyl ester reagents as described in the followingScheme.

[0093] As illustrated in Scheme 4, a haloquinoline couples (1) with anacrolein acetal (7) having a formula CH₂═CHCH(OR⁶)(OR⁷), wherein R6 andR⁷ are independently C₁ to C₆ alkyl, via a palladium-catalyzed reactionin the presence of a base. The reaction is carried out at a temperaturefrom about 90° C. to about 110° C. in a polar aprotic solvent.

[0094] Palladium catalysts suitable for coupling the propargyl alcoholwith the haloquinoline can also be used for the reacting the startingmaterial with the acrolein acetal. Acrolein acetals suitable for thecoupling include, but are not limited to, acrolein dimethylacetal,acrolein diethylacetal, acrolein diisopropylacetal, acroleinn-dibutylacetal, acrolein n-dipentylacetal, acrolein ethylmethylacetal,acrolein isopropylmethylacetal, and the like. Portions of the acroleinacetal used relative to the haloquinoline generally ranges from about1:1 to about 4:1.

[0095] A phosphine is optionally used with the palladium acetatecatalyst. Suitable phosphines are selected from the group as describedabove relating to the coupling of the alkynol in Scheme 1. Preferably,the phosphine for coupling the acrolein acetal with the haloquinoline istri(o-tolyl)phosphine. Portions of the phosphine relative to portions ofthe palladium catalyst generally range from about 1:1 to about 8:1.

[0096] Addition of a phase transfer agent, preferably tetrabutylammoniumhydrogen sulfate, provides the carbonate.

[0097] An inorganic or organic base is suitable for the reaction, andselected from the group described above. The reaction is carried out inan aprotic solvent as previously described.

[0098] The carboxaldehyde acetal (8), wherein R⁶ and R⁷ areindependently C₁ to C₆ alkyl, obtained therefrom is then treated with anacid to produce the acrolein (9). The acid is selected from a widevariety of inorganic and organic acids selected from hydrochloric acid,sulfuric acid, formic acid, acetic acid, propionic acid, butyric acid,tartaric acid, citric acid, trifluoroacetic acid, p-toluensulfonic acid,pyridinium p-toluenesulfonic acid, and the like, or a mixture thereof.

[0099] The preparation of the acrolein allows for using milder reducingagents, such as borane complex reagents, during reduction. Reduction ofthe acrolein with a borane complex reagent provides the alkenol, whichcan be converted into the carbonate or carbamate derivatives of formula(I) as previously described. The reduction is accomplished at roomtemperature in an aprotic solvent selected from the group describedabove for the coupling the alkynol to the haloquinoline. Exemplaryborane complex reagents include, but are not limited to, borane-dimethylsulfide, borane-tetrahydrofuran complex, borane-pyridine complex,borane-morpholine, borane-trimethylamine complex, borane t-butylamine,borane-N,N-diisopropylethylamine, borane dimethylamine,4-(borane-dimethylamino)pyridine, borane-4-ethylmorpholine, andborane-4-methylmorpholine. From about 0.25 to about 1 equivalent ofborane complex is reacted with 1 equivalent of the3-(3-quinolyl)acrolein. The most preferred borane complex reagent isborane t-butylamine.

[0100] Similarly, borohydride reducing reagents are suitable for thereaction. Typical borohydride reducing reagents are selected fromborane, borane-methyl sulfide, borane-methylsulfide with additives suchas BF₃.OEt₂ or B(OMe)₃, 9-borabicyclononane, lithium borohydride, sodiumborohydride alone or with additives such as AlCl₃ or TiCl₄, lithiumborohydride, and potassium borohydride.

[0101] Aluminum hydride reducing reagents, for example diisobutylaluminum hydride and lithium aluminium hydride alone or with AlCl₃, arealso suitable for the reduction.

[0102] The palladium coupling reaction can also be carried out using avinyl ester (10) of the formula CH₂═CHC(O)OR⁵, wherein R⁵ is C₁ to C₆alkyl, for preparing 3-(quinolyl-substituted)-2-propen-1-alkyl ester(11), wherein R⁵ is C₁ to C₆ alkyl. Treating a haloquinoline with avinyl ester and palladium acetate yields the alkyl ester absent the useof a phosphine. The reaction is carried out in an aprotic solvent in thepresence of base with the addition of a phase transfer reagent, such astetrabutylammonium bromide or tetrabutylammonium chloride.

[0103] Exemplary vinyl esters suitable for the reaction include, but arenot limited to, methyl acrylate, ethyl acrylate, and the like.

[0104] The alkenol starting material for the conversion reaction isobtained from the alkyl ester in one of two ways. Direct reduction ofthe alkyl ester with an aluminum hydride reagent as detailed above inScheme 1 provides the alcohol under conditions as previously described.Treating the alkyl ester (11) at ambient temperature with from about 1to about 10 molar equivalents of base for each equivalent of the alkylester affords carboxylic acid (12), which can be further reduced to thealcohol under mild reduction conditions with a boron reducing reagent,such as borohydrides or borane complex reducing agents.

[0105] Various processes yield secondary carbonate derivatives, whichare described in accordance with another aspect of the invention. Thecompounds of the formula:

[0106] wherein R¹ is independently selected from hydrogen and quinolyloptionally substituted with one or more of (i) alkyl, (ii) alkoxy, (iii)aryl, (iv) nitro, and (v) halo; R² is C₁-C₁₀-alkyl; X is —O— or —NR³,wherein R³ is hydrogen, C₁-C₆-alkyl or aryl, or R² and R³ takenttogether form an aromatic or non-aromatic ring; and R⁸ is —CH═CH—R¹¹ or—C≡CR¹¹, wherein R¹¹ is hydrogen or alkyl; can be used as intermediatesin the 6-O-alkylation of macrolide antibiotic and ketolide compounds.Alkylation of the 6-0-position of an erythromycin derivative isaccomplished in a manner similar to the synthesis using the primarycarbonate, as described in the U.S. application Ser. No. 60/140,968.

[0107] The secondary carbonate or carbamate derivatives can be preparedby one of at least two syntheses. In one method, a2-halo-quinoline-3-carboxaldehyde starting material is treated with anorganometallic reagent and an acylating agent to obtain a compound ofthe desired formula. In another method, a quinoline carboxaldehyde isreacted with an organometallic reagent followed by treatment with anorganolithium compound. The compound is reacted with acylating reagentto provide compounds of formula (III), as illustrated below.

[0108] A 2-halo-3-quinoline carboxaldehyde (13) can be reacted with anorganometallic reagent R⁸—M or R⁸—M—X¹, wherein R⁸ is as defined above,M represents a metal, and X¹ is a halide, and treated with an acylatingreagent to provide a protected secondary carbonate. Preferably, thehaloquinoline carboxaldehyde is 2-iodo-3-quinoline carboxaldehyde.Reaction with the organometallic reagent is accomplished in an aproticsolvent. Exemplary organometallic reagents are vinyl magnesium bromide,vinyl magnesium chloride, and the like. A suitable lithium reagent canbe reacted with the product obtained therefrom and followed by asuitable acylating reagent to provide the secondary carbonate.

[0109] Suitable organolithium reagents are alkyl lithium reagents. Thepreferred alkyl lithium reagent is n-butyllithium.

[0110] Reaction of an organometallic reagent with a quinolinecarboxaldehyde (14) and an acylating reagent affords compounds offormula (III). The preferred reagent, quinoline-3-carboxaldehyde, is acommercially available compound. However, the cost for the material isexpensive ($230/5 g, Aldrich, Milwaukee, Wis., U.S.A.). Novel processesfor preparing the starting material provide a more efficient and costeffective synthesis and can be used for the preparation of a quinolinecarboxaldehyde material or in accordance with a process for preparingquinoline-substituted carbonate, as illustrated below.

[0111] The starting material for the carboxaldehyde synthesis (13),wherein X¹ is a halide, can be prepared by Vilsmeier-Haack formylationof an acetanilide as described by Meth-Cohn, et al. in J. C. S. PerkinI, 1520-1530 (1981). The quinoline-2-halo-3-carboxaldehyde is isolatedand dried to obtain the starting material or, alternatively, an alcoholor orthoformate reagent is directly charged into the reaction mixture toobtain the quinoline-2-halo-3-carboxaldehyde acetal (16), wherein R⁹ andR¹⁰ are independently C₁ to C₆ alkyl.

[0112] Reagents useful for the reaction are alcohols represented by theformula R⁹—OH or orthoformates represented by the formula HC(OR¹⁰)₃,wherein R⁹ is C₁ to C₆ alkyl and R¹⁰ is C₁ to C₃ alkyl. An alcoholsuitable for the invention is selected from methanol, ethanol,isopropanol, butanol, pentanol, and hexanol, or a mixture thereof.Examples of useful orthoesters are trimethyl orthoformate, triethylorthoformate, triisopropyl orthoformate, and the like. Trace amounts oforganic or inorganic acid facilitate the conversion, such as thosetypically selected from acetic acid, formic acid, p-toluenesulfonicacid, hydrochloric acid, phosphoric acid, sulfuric acid, and the like.

[0113] Removing the halo group of the quinoline-2-halo-3-carboxaldehydeacetal is accomplished by treatment with a metal catalyst and hydrogenin the presence of a base. The metal catalysts include, but are notlimited to, palladium, organopalladium, and platinum-based compounds.Examples of suitable metal catalysts are palladium black oxide,palladium on charcoal, palladium acetate, palladium chloride,triarylphosphine palladium complexes, platinum black oxide, and thelike. A summary of suitable reagents and conditions for metal-catalyzedcoupling reactions are described in Heck et al., J. Org. Chem., 1972 37,2320.

[0114] The reaction is carried out in an organic solvent in the presenceof from about 1 to about 6 molar equivalents of base relative to thecarboxaldehyde acetal starting material. Preferably, about 4 molarequivalents of base is used. Exemplary solvents used are organicsolvents, such as acetonitrile, N,N-dimethylformamide,N-methylpyrrolidinone, methanol, ethanol, isopropanol, and the like, ora mixture thereof. Organic base, for example amines, and inorganic basesare suitable for the reaction. Amines that are useful include, but arenot limited to, secondary and tertiary amines, such as dimethylamine,diethylamine, triethylamine, diisopropylethylamine,diethylaminopyridine, and pyridine. Inorganic bases are selected fromsodium hydroxide, potassium hydroxide, ammonium hydroxide, sodiumcarbonate, potassium carbonate, ammonium carbonate, and the like.

[0115] The carboxaldehyde (14) is obtained from carboxaldehyde acetal(17) by hydrolysis with an acid carried out in organic or inorganicsolvent. The acids are organic and inorganic acids. Suitable inorganicacids include sulfuric acid, hydrochloric acid, and the like. Thepreferred solvents are organic solvents, such as methanol, ethanol,isopropanol, and the like. Preferably, the weak acids are formic acidand acetic acid.

[0116] The carboxaldehyde provides a suitable starting material for thesynthesis of the primary and secondary carbonate derivatives. Theaddition of an organometallic reagent compound to the carboxaldehydegenerates an intermediate complex, which is coupled to an acylatingreagent, for example di-tert-butyl dicarbonate and di-isopropyldicarbonate, to prepare a carbonate. Other exemplary acylating reagentsare as described above. Carbamate derivatives of the invention can beprepared by using carbamoyl chlorides or acid chlorides of aromatic ornon-aromatic nitrogen heterocycles.

[0117] Suitable organometallic reagents are represented by the formulaR⁸—M and R⁸—M—X¹, wherein R⁸ is substituted or unsubstituted C₁-C₆alkenyl or C₁-C₆ alkynyl, such as substituents of the formula —CH═CH—R¹¹and —C≡C—R¹¹, wherein R¹¹ is hydrogen or alkyl, M represents a metal,and X¹ is a halide. Preferably, the organometallic reagent used is anorganolithium or an organomagnesium reagent, such as a Grignard reagent.The preferred reagents are selected from reagents of the formulas R⁸—Mand R⁸—M—X¹, wherein M is lithium or magnesium and X is bromine,chlorine, and iodine. Common Grignard reagents as described inaccordance with the Y. H. Lai, Synthesis 1981, 104, which is hereinincorporated by reference. Exemplary organometallic reagents are t-butyllithium, diethylmagnesium, ethynylmagnesium bromide, ethynylmagnesiumchloride, vinylmagnesium bromide, vinylmagnesium chloride, and the like.

[0118] The reaction is accomplished in an aprotic solvent selected fromthe group described above for the preparation of the alkynol. Suitabletemperatures for the reaction are from about −10° C. to about −15° C.

[0119] Alkyne-1-substituted quinoline compounds of formula (II), whereinR⁸ is —C≡C—R¹¹ can be optionally reduced to the correspondingalkenyl-substituted carbonate by a palladium-catalyzed hydrogenationreaction using hydrogen gas. The preferred palladium catalyst forreducing the alkyne-1-substituted quinoline carbonate is Lindlar'scatalyst (5% palladium on calcium carbonate poisoned with lead orPd/CaCO₃/Pb).

[0120] The reaction is carried out in a polar organic solvent selectedfrom the group consisting of tetrahydrofuran, N,N-dimethylformamide, andisopropanol.

[0121] The carboxaldehyde (14) can also undergo condensation with anacetate ester (18), wherein R⁵ is C₁ to C₆ alkyl, with either an organicor inorganic base to provide a primary carbonate or carbamate, which isdescribe in accordance with the Scheme 7 below.

[0122] A suitable acetate ester for the reaction is represented by theformula H₃C—C(O)(OR⁵), (18) wherein R⁵ is C₁ to C₆ alkyl, selected frommethyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, and thelike. Preferably, about 0.5 molar equivalents to about 2 molarequivalents of base are used relative to the carboxaldehyde. Typicalbases for the reaction include, but are not limited to, potassiumt-butoxide, sodium t-butoxide, sodium hydride, potassium carbonate,sodium ethoxide, sodium methoxide, 1,8-diazabicyclo[5.4.0]undec-7-ene,sodium hexamethyldisilazane, lithium hexamethyldisilazane, lithiumdiisopropylamide, and the like. Potassium t-butoxide is the preferredbase.

[0123] Condensation of acetaldehyde with the carboxaldehyde (14) affordsthe acrolein intermediate (9) using relatively inexpensive reagents. Thecondensation can be carried out with acetic anhydride in the presence ofan acid. Reduction of the product obtained therefrom provides thecorresponding alkenol. The preferred method for reducing the acroleinintermediate is reduction with a borohydride reagent, such as sodiumborohydride.

[0124] The processes described for the invention are particularly usefulfor preparing 3-(3-quinolyl)-2-propenyl derivatives, which are compoundsof formula (I) and have the preferred structure for the 6-O-allylationreaction of macrolide antibiotics. To obtain3-(3-quinolyl)-2-propen-1-ol t-butyl carbonate, for example,3-bromoquinoline is coupled with propargyl alcohol, and reduced bymethods of catalytic semi-hydrogenation to obtain3-(3-quinolyl)-2-propen-1-ol. The 3-(3-quinolyl)-2-propen-1-ol iscoupled with an acylating reagent capable of placing a t-butyl group onthe oxygen atom of the terminal hydroxy group, preferably di-tert-butyldicarbonate, to afford 3-(3-quinolyl)-2-propen-1-ol t-butyl carbonate.

[0125] In another preferred process, the 3-(3-quinolyl)-2-propyn-1-ol iscoupled with an acylating reagent to provide a carbonate or carbamatederivatives, which can be hydrogenated to provide a compound of formula(I). The preferred acylating reagent for the reaction is di-tert-butyldicarbonate.

[0126] In yet another preferred process, the 2-chloro-3-quinolinecarboxaldehyde is converted into 2-iodo-3-quinoline and reacted withvinyl magnesium bromide followed by n-butyllithium and an acylatingagent, preferably di-tert-butyl dicarbonate. The1-(3-quinolyl)-2-propen-1-ol t-butyl carbonate prepared by the processis a compound of formula (II).

[0127] The processes for preparing a compound of formula (I) via thealkenol intermediate can be generally described as comprising the stepsof:

[0128] (a) preparing a compound of the formula R¹—CH═CHCH₂OR⁴, whereinR¹ and R⁴ are as previously defined;

[0129] (b) optionally deprotecting the compound obtained in step (a);and

[0130] (c) reacting the compound of the formula R¹—CH═CHCH₂OH with anacylating agent.

[0131] An alternative process for preparing the compounds of formula (I)comprises:

[0132] (a) preparing a compound of the formula R¹—C≡C—CH₂—OC(O)—X—R²,wherein R¹ and R² are as previously defined; and

[0133] (b) hydrogenating the compound obtained in step (a).

[0134] The alternative process allows for preparation of the carbonateand carbamate derivatives by directly coupling a propargyl alcoholderivative with an acylating reagent and hydrogenating the alkyne bondto obtain a desired compound.

[0135] In another aspect, the invention relates to a compound having theformula

R¹—CH═CHCH₂OC(O)—X—R²  (I)

[0136] wherein

[0137] X is —O— or —NR³—;

[0138] R¹ is independently selected from hydrogen and quinolyloptionally substituted with one or more substituents selected from:

[0139] (i) alkyl,

[0140] (ii) alkoxy,

[0141] (iii) aryl,

[0142] (iv) nitro, and

[0143] (v) halo;

[0144] R² is C₁-C₁₀-alkyl;

[0145] R³ is hydrogen or C₁-C₆-alkyl; or R² and R³ taken together forman aromatic or non-aromatic ring; and

[0146] R⁸ is selected from:

[0147] (i) —CH═CH—R¹¹; and

[0148] (ii) —C═CR¹¹, wherein R¹¹ is hydrogen or alkyl.

[0149] The invention also relates intermediate compounds having theformula:

[0150] (a) R¹—CH═CHC(O)OR⁵, wherein R¹ is independently selected fromhydrogen and quinolyl optionally substituted with one or substituentselected from (i) alkyl, (ii) alkoxy, (iii) aryl, (iv) nitro, and (v)halo; and R⁵ is C₁ to C₆ lower alkyl;

[0151] (b) R¹—CH═CHCH(OR 6)(OR 7), wherein R⁶ and R⁷ are independentlyC₁ to C₆ alkyl;

[0152] (c) R¹—CH═CHC(O)OH;

[0153] (d) R¹—CH═CHCHO;

[0154] (e) R¹—C≡C—CH₂—OC(O)—X—R²; wherein R² is C₁-C₁₀-alkyl; X is —O—or —NR³; and R³ is hydrogen, C₁-C₆-alkyl or aryl; or R² and R³ takentogether form an aromatic or non-aromatic ring; or

[0155] (f) R¹—CH═CHCH₂OH.

[0156] The intermediates are prepared by processes previously describedand provide useful compounds in obtaining the desired carbonates andcarbamates of formulas (I), (II) and (III).

[0157] Processes of the invention are better understood by reference tothe following Reference Example and Examples. Various changes andmodification may be made by one having ordinary skill in the art withoutdeparting from the scope of the invention. The Reference Example and theExamples are intended to provide illustration for a better understandingof the invention and are not meant to limit the invention in any way.

EXAMPLES Reference Example 1

[0158] The following Reference Example illustrates a method forpreparing the quinoline-2-chloro-3-carboxaldehyde compound, which can beused as a starting material for the preparation ofquinoline-3-carboxaldehyde.

Reference Example 1 Quinoline-2-chloro-3-carboxaldehyde

[0159] To a 1-L three-necked flask equipped with mechanical stirrer,temperature probe, pressure equalizing dropping addition funnel, and drynitrogen line was charged with dimethyl formamide (54.1 g, 0.74 mol).The contents were cooled to 0-5° C. in an ice/salt/water bath.Phosphorous oxychloride (317.5 g, 2.07 moles) was slowly charged intothe mixture while monitoring the internal temperature of NMT +10° C. Theaddition typically required 30 minutes. The resultant slurry was mixedat 0-5° C. for 30 minutes. Acetanilide (40.0 g, 0.296 mol) was chargedin a single portion via the pressure equalizing dropping additionfunnel. The cooling bath was removed and the reaction mixture was warmedto 75° C. The reaction was monitored by thin layer chromatography (40:60ethyl acetate/heptane). After completion of the reaction, the mixturewas cooled to room temperature and then transferred to a droppingaddition funnel. The mixture was added dropwise to 1.5 liter of watercooled to 0-5° C. contained in a 3-L three-necked flask equipped withmechanical stirrer and cooled in an ice/salt/water bath. The resultantyellow slurry was stirred at 0-5° C. for 30 minutes, and then filtered.The solid was filtered and washed with water to neutrality, then airdried. The solid was then dried in a vacuum oven at 40° C. over a periodof 2 days to yield 39.0 g of product as a light yellow, powdery solid.

Examples 1-8

[0160] Examples 1-8 illustrate methods for preparing3-(3-quinolyl)-2-propen-1-ol t-butyl carbonate of formula (I).

Example 1 Preparation of 3-(3-Quinolyl)-2-Propen- 1-ol t-Butyl Carbonate

[0161] Step (1): Preparation of 3-(3-quinolyl)-2-propyn-1-ol (Scheme 1,Compound (2))

[0162] To a dry 2-L three-necked flask previously purged with nitrogenwas charged 3-bromoquinoline (118.77 g, 570 mmol), propargyl alcohol(71.9 g, 1.28 mol, 2.25 equiv), triethylamine (1500 mL), copper(I)iodide (3.62, 19 mmol, 0.033 equiv) and dichlorobis(triphenyl-phosphine)palladium(II) (6.67 g, 9.5 mmol). The mixture which resulted wasmechanically stirred and heated to reflux for 3 hours. Upon cooling thetriethylamine solution was mechanically stirred and heated to reflux for3 hours. Upon cooling, the triethylamine solution was filtered andwashed with triethylamine (300 mL). The filtrate was then concentratedunder reduced pressure to provide solids which were suspended in 5% aq.NaHCO₃ (600 mL) and extracted with ethyl acetate (1×600 mL). The solidswhich were left after filtration were treated in the same manner. Thecombined ethyl acetate extracts were stirred with silica gel (15 g) anddecolorizing carbon (3 g) before being filtered through a bed of celite.The filtrate was concentrated under reduced pressure to provide a tancolored solid which was vacuum oven dried at 45° C. overnight. The3-(3-quinolyl)-2-propyn-1-ol was isolated in 92.14 g (88.3% yield).MS(CI): (M+H)⁺ at 184; ¹H NMR (300 MHz CDCl₃)δ:4.56 (s, 2H), 4.70 (s,broad, 1H), 7.57 (m, 1H), 7.70 (m, 1H), 7.77 (d, 1H), 8.10 (d, 1H), 8.10(s, 1H), 9.05 (s, 1H).

[0163] Step (2A): Preparation of cis 3-(3-quinolyl)-2-propen-1-ol(Scheme 2, Compound (3-cis))

[0164] To a 1-L three-necked round-bottom flask was charged3-(3-quinolyl)-2-propyn-1-ol (31.65 g, 173 mmol), ethanol (550 mL) and5% palladium on calcium carbonate poisoned with lead (Lindlar'scatalyst, 750 mg, 0.024 equiv). The atmosphere above the heterogeneousmixture was purged with hydrogen after which time hydrogen was deliveredto the reaction via a balloon. The progress of the reaction wasmonitored by TLC (1:1 ethyl acetate/heptane). Upon reaction completion(˜16 hours), the mixture was purged with nitrogen and vacuum filteredthrough a bed of celite. The product filtrate was then concentratedunder reduced pressure. The residue which resulted was dissolved inethyl acetate (750 mL) and extracted with 2 N HCI (2×750 mL). Theaqueous acidic product solution was then adjusted to pH 9 with 2 N NaOHand then back extracted with isopropyl acetate (2×700 mL). The organicwas then dried over Na₂SO₄, filtered and concentrated to an oil underreduced pressure. The product oil 3-(3-quinolyl)-2-propene-1-ol (29.5 g,92.2%), which consisted of a mixture of both cis- and trans- alkenols,was subjected to flash chromatography (1:1 ethyl acetate/heptane) toisolate pure cis- alkenol. Both the cis- and trans- alkenols wereisolated and submitted for ¹H NMR analysis. The coupling constant Jabfor the cis- alkenol was found to be 11.67 Hz while J_(ab) for thetrans- alkenol was found to be 15.93 Hz.

[0165] Step (2B): Preparation of trans 3-(3-quinolyl)-2-propen-1-ol(Scheme 2, Compound (3-trans))

[0166] To a dry, jacketed 250-mL three-necked round-bottom flask wascharged sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al, 70% wt.solution in toluene, 11.0 g, 38.1 mmol, 1.39 eq) and anhydrous THF (20mL). To this precooled (0-2° C.) and magnetically stirred solution wasadded a THF (50 mL) solution of the 3-(3-quinolyl)-2-propyn-1-ol (5.0 g,27.32 mmol) via pressure equalizing dropping funnel. The temperature wasnot allowed to rise above 15° C. After the addition was complete (20minutes) the mixture was allowed to warm up to room temperature andstirred for one hour. The solution was then cooled to 0° C. and quenchedby the addition of aqueous 10% sulfuric acid (20 mL) such that theinternal temperature did not rise above 15° C. The biphasic reactionmixture was then washed with ethyl acetate (3×100 mL). The pH of theaqueous acidic product solution was then adjusted to pH 9-10 with aq.conc. NH₄0H and back extracted into ethyl acetate (2×125 mL). Thecombined organic layers were dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure to give exclusively3-(3-quinolyl) trans-2-propen-1-ol as a solid: 4. 1 g, 81%.

[0167] Step (3): Preparation of 3-(3-quinolyl)-2-propen-1-ol t-butylcarbonate (Scheme 1, Compound (I))

[0168] To a 500-mL three-necked round-bottom flask equipped with anoverhead mechanical stirrer was charged 3-(3-quinolyl)-2-propen-1-ol(13.03 g, 70.43 mmol) as a mixture of cis- and trans- isomers (81% cis,and 19% trans), di-tert butyl dicarbonate (16.91 g, 77.48 mmol, 1.11equiv), tetra n-butylammonium hydrogen sulfate (742 mg, 2.17 mmol) andmethylene chloride (135 mL). The stirred mixture which resulted wascooled to 0 to 5° C. at which time aqueous 25% sodium hydroxide (33.3mL) was added over 45 minutes such that the internal temperature did notrise above 20° C. Upon completion of the reaction (1 to 4 hours) asindicated by TLC (3:2 ethyl acetate/heptane), the reaction mixture wasdiluted with methylene chloride (50 mL) and washed with water (2×125mL). The organic was dried over anhydrous sodium sulfate, filtered, andconcentrated in vacuo to provide the3-(3-quinolyl)-2-propen-1-ol-t-butyl carbonate: 18.35g, 91.4% as an oil.This material can be further purified to remove lower R_(f) impuritiesby eluting through a plug of silica gel withheptane/acetone/triethylamine (9:1:0.1). The product eluant is thenconcentrated under reduced pressure and further dried by theazeodistillation of ethyl acetate. This procedure provides the purifiedcarbonate as a colorless oil which retains the original ratio of cis andtrans isomers: 17.50 g, 87.2%.

Example 2 Preparation of 3-(3-Quinolyl)-2-Propen- 1-ol t-Butyl Carbonate

[0169] Step (1): Preparation of 3-(3-quinolyl)-2-propyn-1-ol t-butylCarbonate

[0170] To a dry 1-L three-necked round-bottom flask equipped with anitrogen inlet and overhead stirrer was charged3-(3-quinolyl)-2-propyn-1-ol (15.81g, 86.39 mmol), di-tert-butyldicarbonate (22.48g, 103 mmol, 1.19 equiv), n-tetrabutyl ammoniumhydrogen sulfate (0.86 g, 2.54 mmol, 0.029 equiv) and methylene chloride(300 mL). The resulting suspension was mechanically stirred while a 25%w/w aqueous NaOH solution (38 g) was added in over a period of 5minutes. The biphasic mixture which resulted was stirred for 4 hoursafter which time the reaction was found to be complete by HPLC and TLC.The mixture was diluted with water (200 mL) and methylene chloride (100mL). After stirring for 10 minutes and settling for 15 minutes thelayers were separated. The organic layer was washed with water (1×200mL) and 20% aq., NaCl (1×200 mL). The organic was then stirred with 15 gof sodium sulfate, filtered and then stripped to an oil under reducedpressure. The residual oil was taken up in isopropyl acetate/hexane (1:1, 100 mL) and passed through a small pad of silica gel (8 g). The padwas rinsed with the same eluent (100 mL). The combined filtrates wereconcentrated under reduced pressure and rigorously dried in a vacuumoven to yield the 3-(3-quinolyl)-2-propyn-1 ol t-butyl carbonate as alight orange-yellow colored oil: 24.50 g, 100%.

[0171] Step 2: Preparation of 3-(3-quinolyl)-2-propen-1-ol t-butylcarbonate (Compound (I))

[0172] To a 250-mL single-necked round-bottom flask was charged the3-(3-quinolyl)-2-propyn-1-ol t-butyl carbonate (1.52 g, 5.37 mmol),isopropanol (30 mL) and 5% palladium on calcium carbonate poisoned withlead (Lindlar's catalyst, 75 mg, 0.049 equiv). The suspension wasstirred (rapidly) magnetically and the atmosphere above the solution waspurged with hydrogen. A balloon of hydrogen gas was then placed over thereaction stirring mixture and the reaction was allowed to stir for 16hours at room temperature. The reaction mixture was then filteredthrough a 0.45 μ filter disk and rinsed with 10 mL of isopropanol. Thecombined filtrates were concentrated under reduced pressure and theresidue (1.55 g) was taken up in 9 mL of heptane/acetone (8: 1) andeluted through a plug of silica gel (1.5 g) with 8:1:0.01heptane/acetone/triethylamine. The desired fractions were combined andconcentrated under reduced pressure to provide3-(3-quinolyl)-2-propen-1-ol t-butyl carbonate: 1.1 g, 71.9%

Example 3 Preparation of 3-(3-Quinolyl)-2-Propen-1-ol t-Butyl Carbonate

[0173] Step (1): Preparation of 3-(3-quinolyl)-2-propyn-1-ol

[0174] A 1-L three-necked round-bottom flask was charged with 37.2 gtetra-n-butyl ammonium bromide, 19.62 g palladium on carbon (5% loading,50% wet with water), and 3.60 g of triphenylphosphine. The flask wasfitted with a reflux condensor, a thermometer, a pressure equalizingaddition funnel and a nitrogen inlet adapter. The solids were degassedby application of vacuum to the falsk and venting with nitrogen (processrepeated 3 times). Piperidine (69.0 g), acetonitrile (132 g) and3-bromoquinoline (48.0 g) were added and the reaction mixture heated to50° C. Propargyl alcohol (22.8 g) was added dropwise over 15 minutes,with no appreciable exothern being observed. The reaction mixture wasstirred at 50° C. until HPLC monitoring revealed the reaction to becomplete (about 8 hours).

[0175] Once complete, the reaction mixture was hot-filtered (to removethe catalyst) through a ½″ plug of filtrol filtering aid. The collectedsolids were washed with 50 mL of isopropanol. The combined filtrateswere slowly added to 1.5 L of rapidly stirring distilled deionizedwater. The mixing continued for 10 minutes past the completion of theaddition and the solid product was collected by filtration. The filteredsolids were washed twice with 150 mL of distilled deionized water anddried in vacuo (nitrogen purge, oven temperature below 50° C.) overnightaffording 41.85 g (99% yield) of a brownish yellow solid. Measuredpotency 85% versus known standard.

[0176] Step (2): Preparation of 3-(3-quinolyl)-2-propen-1-ol

[0177] The 3-(3-quinolyl)-2-propyn-1-ol from above is reduced to thealkenol by either the hydrogenation method (Example 1, Step (2A)), orRed-Al method (Example 2, Step (2B)).

[0178] Step (3): Preparation of 3-(3-quinolyl)-2-propen-1-ol t-butylCarbonate

[0179] The alkenol from above is converted into the3-(3-quinolyl)-2-propen-1-ol t-butyl carbonate in accordance with themethod described in Example 1, Step (3).

Example 4 Preparation of cis-3-(3-Quinolyl)-2-Propen-1-ol t-ButylCarbonate

[0180] Step (1): Preparation of Cis-3-(3-guinolyl)-2-propen-1-ol

[0181] To a dry 3000-mL three-necked jacketed flask, equipped with athermocouple was charged 3-(3-quinolyl)-2-propyn-1-ol (76 g, 415.3 mmol)(Example 3, Step (1)), 5% Pd/CaCO₃ (1.52 g) and3,6-dithia-1,8-octanediol (0.76 g). 3A Ethanol (1125 mL) was thencharged and the mixture which resulted was vigorously stirred at ambienttemperature (19° C.). The atmosphere above the mixture was purged withhydrogen and then evacuated. This purging and evacuating process wasrepeated twice. Hydrogen balloons (0.32 psi) were placed above thereaction mixture and the progress of the reduction was monitored by HPLCanalysis. After 25 hours, the reaction was stopped.

[0182] The mixture was filtered through a bed of diatomaceous earth andthe flask and cake were washed with 3A ethanol. The filtrate wasconcentrated under reduced pressure. The residue was dissolved in methylisobutyl ketone (MIBK, 400 mL) and this solution was passed through aplug of Filtrol (38 g). MIBK (125 mL) was used to rinse the flask andcake until the filtrate was colorless. The combined filtrates wereconcentrated to a volume of 200 mL then diluted with MIBK (270 mL) atwhich time the crystallization of the cis-PQ alcohol was initiated. Thecrystallizing solution was then slowly triturated with heptanes (270 mL)with stirring and later cooled to 0° C. overnight. The product waswashed with cold MIBK/heptanes (3:4, 150 mL). The wet cake was vacuumoven dried at 50° C. for 6 hours to givecis-3-(3-quinolyl)-2-propen-1-ol (50.0 g, 70.0% yield, adjusted forpotency of starting material). Purity as determined by HPLC was 98.9%.

[0183] Step (2): Protection of cis-3-(3-quinolyl)-2-propen-1-ol

[0184] The solid cis-3-(3-quinolyl)-2-propen-1-ol (10.0 g, 54.1 mmol),di-tert-butyl dicarbonate (17.6 g, 80.6 mmol, 1.5 equiv), toluene (43 g)and tetra n-butylammonium hydrogen sulfate (0.68 g, 2.0 mmol) werecombined and stirred (mechanically) in a three-necked round-bottomflask. To this stirring mixture was slowly added an aqueous sodiumhydroxide solution (28 g H₂O and 7.0 g, NaOH) over 10 minutes. Thetemperature of the biphasic mixture warmed from 18° C. to 31° C. for 1.5hours and then allowed to stir overnight at room temperature. Thereaction was then diluted with toluene (33 mL) and water (19 mL). Thelayers were separated (aq. pH 12) and the organic was washedconsecutively with water (1×28 mL) and 5% aq. NaCl (1×28 mL). The pH ofthe aqueous layers were 10 and 9 respectively. The organic was thenwashed with an aqueous sodium chloride solution (7 g NaCl, H₂O 28 g)before concentration under reduced pressure and a bath temperature of50° C. The oil which resulted was chased with heptane (2×100 g). Theresidue was dissolved in 55 mL of heptane to initiate crystallization.This product was collected at −5° C., washed with cold heptane (10 mL)and vacuum dried at room temperature to provide a white to off whitecolored solid (13.6 g, 88.3%). Purity as determined by HPLC was 98.7%.

Example 5 Preparation of Cis-3-(3-Quinolyl)-2-Propen-1-ol t-ButylCarbonate

[0185] To a 30 gallon reactor was charged 3-(3-quinolyl)-2-propyn-1-ol(5000 g, 27.3 mol) (Example 3, Step (1)), 5% Pd/CaCO₃-Pb (100 g) and3,6-dithia-l,8-octanediol (50 g). The reactor was vented and purged withnitrogen three times before anhydrous ethanol (75 L, 60 kg) was charged.The mixture which resulted was stirred at 2 psi of hydrogen pressure andat a jacket temperature of 18° C. for 23 hours. Upon reactioncompletion, the pressure was released and the reactor was vented andpurged with nitrogen three times prior to filtration. The mixture wasthen filtered through a bed of celite. The reactor was splashed with 20kg (25 L) of ethanol and passed through the filter also. The combinedproduct filtrates were colleceted in a tared polylined drum and held forfuther processing.

[0186] To a 50 gallon reactor was charged tetrabutylammonium hydrogensulfate (0.34 kg, 1.0 mol) and the ethanolic hydrogenation solution(27.3 mol). The ethanol was distilled off under vacuum and ajackettemperature of NMT 60° C. The residue was dissolved in toluene (25) andagain concentrated under reduced pressure with a jacket temperature ofNMT 65° C. The residue was again dissolved in toluene (18 kg) andanalyzed by GC for the presence of ethanol. Di-tert-butyl dicarbonate(8.9 kg, 40.8 mol) and toluene (18 kg) was charged to the reactor andthe internal temperature was raised to NMT 30° C. An aqueous sodiumhydroxide solution (3.4 kg NaOH and 14 kg water) was then slowly chargedto the reaction mixture maintaining an internal temperature of NMT 40°C. During the reaction, the biphasic suspension completely dissolved togive a clear amber colored solution. The reaction was allowed to proceeduntil determined by complete HPLC.

[0187] The solution was diluted with toluene (16.4 kg) and water (9.4kg). The organic layer was separated and washed with water (2×14 kg) and25% aq. sodium chloride (17.5 kg). The organic solution was thenfiltered through a bed of celite. The toluene product filtrate wasdistilled under vacuum and a jacket temperature of NMT 65° C. Toluene(14 kg) was charged back to dissolve the residue. The solution was thendrained to clean and tared polypropylene carboy followed by a toluenerinse. The overall two step yield was 92%.

Example 6 Preparation of 3-(3-Quinolyl)-2-Propen-1-ol t-Butyl Carbonate

[0188] To a 100-mL round-bottom flask was charged the tetrahydropyranylprotected 3-(3-quinolyl)-2-propyn-1-ol (1.92 g, 7.19 mmol), Lindlar'scatalyst (77 mg) and anhydrous ethanol (22 mL). The mixture whichresulted was magnetically stirred under an atmosphere of hydrogen gas(balloon, 0.3 psi) for 46 hours. The reaction was tracked by HPLC andTLC and was terminated after partial conversion to the product (12%product, 88% starting material). The mixture was filtered to remove thecatalyst and the filtrate was concentrated under reduced pressure togive an oil 1.95 g. The tetrahydropyranol protected3-(3-quinolyl)-2-propen-1-ol was deprotected by standard methods andtreated in accordance with the method described in Example 1, Step (1)to obtain the title compound.

Example 7 Preparation of 3-(3-Quinolyl)-2-Propen-1-ol t-Butyl Carbonate

[0189] Step (1): Heck coupling of 3-bromoquinoline with acroleindiethylacetal (Scheme 4, Compound (9))

[0190] A mixture of 3-bromoquinoline (2 g, 9.6 mmol), acroleindiethylacetal (1.5 g, 11.5 mmol), tri(o-tolyl)phosphine (0.23 g, 0.76mmol) and palladium acetate (43 mg, 0.2 mmol) in triethylamine (6 ml)was heated under nitrogen at 100° C. for 4 hours. TLC showed thereaction was complete. The crude product corresponded to Compound (8),of Scheme 4. After cooling to room temperature, the mixture was quenchedwith 15 ml of dilute HCI, and the product was extracted with 10 ml ofmethylene chloride. The organic layer was washed with 15 ml of water,filtered to remove insolubles and concentrated under vacuum to give alight brown oil (1.35 g). Column chromatography (silica gel, 20:80 ethylacetate/hexane) gave 3-(3′-quinolyl)acrolein (0.75 g, 42.6%) (compound(9), Scheme 4) as light yellow crystals. MS(M+H⁺)=184; H¹ NMR(ppm): 6.93(1H, dd), 7.6 (1H, dd), 7.62 (1H, dd), 7.8 (1H, m), 7.9(1H, dd), 8.15(1H, d), 8.32 (1H, d), 9.12 (1H, d), 9.8 (1H, d).

[0191] Step (2): Reduction of 3-(3′-quinolyl)acrolein with boranet-butylamine (Scheme 4, Compound (6))

[0192] Borane t-butylamine (0.06 g, 0.7 mmol) was added to a stirredsolution of 3-(3′-quinolyl)acrolein (0.32 g, 1.7 mmol) intetrahydrofuran (10 ml) at room temperature. The mixture was stirred atroom temperature for 90 minutes, quenched with 10 ml of water andextracted with 2×20 ml ethyl acetate. The organic layers were combinedand washed with 10 ml of water and concentrated to give3-(3′-quinolyl)allyl alcohol (0.3 g).

[0193] Step (3): Preparation of 3-(3-quinolyl)-2-propen-1-ol t-butylCarbonate

[0194] The 3-(3′-quinolyl)allyl alcohol was treated in accordance withStep (3) of Example 1 to obtain the title compound.

Example 8 Preparation of 3-(3-Quinolyl)-2-Propen-1-ol t-Butyl Carbonate

[0195] Step (1): Preparation of 3-(3-quinolyl)-2-propenoate (Scheme 4,Compound (11))

[0196] The 3-bromoquinoline (300 g, 1.44 mmol), ethyl acrylate (168 g,1.68 mmol), palladium(II) acetate (32.3 g, 144 mmol), tetrabutylammoniumbromide (478 g 1.44 mol), and sodium bicarbonate (483.9 g, 5.76 mol)were combined in a 5-L round-bottom flask with overhead stirring and 3 Ldimethyl formamide (anhydrous). The reaction mixture was heated to 90°C. with heating mantle. After 30 minutes, 3-bromoquinoline was notdetected by HPLC. The reaction was cooled to room temperature with anice bath, and 2.65 L of ethyl acetate was added. The organic layer waswashed with 1500 mL H₂O. The aqueous layer was extracted with 4×1 L of1:1 toluene/ethyl acetate; the combined organic layers were then washedwith 6×1 L brine, then evaporated to give 217.4 g (65% of desiredproduct).

[0197] Step (2): Preparation of 3-(3-quinolyl)-2-propen-1-ol (Scheme 4Compound (6))

[0198] The 3-(3-quinolyl)-2-propenoate (141 g, 0.621 moles) wasdissolved in 2.0 L anhydrous methylene chloride in a 5-L round-bottomflask with overhead stirring and cooled to −57° C. with isopropanol/dryice bath. Diisobutylaluminum hydride (1.55 L, 1.0 M in methylenechloride) was added in a slow stream, keeping the temperature of thereaction mixture below −40° C. After 30 minutes, the starting ester isconsumed. While cooling with dry ice/acetone, 434 mL MeOH was addeddropwise and the mixture was allowed to warm to room temperature. Then,2 L of 10% sodium potassium tartrate was added portionwise to thesolution and the mixture was stirred for 1 h at room temperature. Thelayers were separated. The organic layer was washed with 2 L aq. NaClsolution and dried over MgSO₄. Evaporation gave a solid which wasrecrystallized from EtOAc to afford a yield of 71 g (62%) of a pinkishsolid.

[0199] Step (3): Preparation of 3-(3-quinolyl)-2-propen-1-ol t-butylcarbonate (Scheme 4 Compound (I))

[0200] Allylic alcohol (115.4 g, 623 mmol), di-tert-butyl dicarbonate(163.2 g, 748 mmol), and tetrabutylammonium hydrogen sulfate (6.35 g,18.7 mmol) were combined in 721 mL methylene chloride, cooled to 0-5°C., and sodium hydroxide (92.7 g, 2.32 moles) in 293 mL H₂O was added.The reaction was stirred under nitrogen and allowed to warm to r.t.overnight. The mixture was partitioned between H₂O and methylenechloride (310 mL each). The aqueous layer was extracter with another 200mL methylene chloride. The combined organic layers were washed withbrine, dried with Na₂SO₄, filtered and evaporated to give 285.8 g ofcrude material which was purified by silica gel chromatography 20/80ethyl acetate/hexanes to give 136.7 g (81%) of3-(3-quinolyl)-2-propen-1-ol t-butyl carbonate.

Example 9 Preparation of 3-(3-Quinolyl)-2-Propen-1-ol t-Butyl Carbonate

[0201] To a 1-L three-necked round-bottom flask equipped with mechanicalstirrer, J-Kem temperature probe, transfer cannula, and dry nitrogenline was charged 3-(3-quinolyl)-2-propenoate (18.78 g, 88.07 mmol, 1.0equiv) and 370 mL (19.7 mL/g) of dry methylene chloride. The contentswere mixed to dissolve and then cooled to −50±5° C. A solution of DIBALin toluene (99.82 g of 25 wt. % solution; 25.0 g active DIBAL, 175.78mmol, 2.00 equiv) was slowly charged over 2 hours, and the temperaturewas maintained at NMT −45° C. during the addition. An HPLC sample wastaken at T=2 hours, and revealed that the reaction was complete.

[0202] The reaction was quenched by the slow addition of 19 mL ofmethanol, maintaining a temperature of NMT −30° C. This was followed bya charge of 200 mL of a 15% solution of potassium sodium tartarate,again maintaining a temperature of NMT −30° C. during the addition. Thereaction mixture was then warmed to 0° C. and stirred at temperature for1 hour. The cooling bath was removed and the reaction mixture wasallowed to warm to room temperature with stirring overnight. Thefollowing morning the aqueous phase was removed and discarded. Theorganic phase was washed 2×95 mL with water.

[0203] The combined organic phases were cooled to 0 to 5° C. then 25.0 gof BOC (t-butyloxy-carbonyl) anhydride was added, followed by 1.2 g oftetrabutylammonium hydrogen sulfate, and 55 mL of 25% aqueous sodiumhydroxide. The cooling bath was removed and the reaction mixture wasallowed to warm to room temperature, with stirring, overnight. HPLC atT=16.5 hours revealed 2.2% remaining starting material. An additional3.8 g of BOC anhydride was charged. A resample at T=19.5 hours reveals0.8% remaining starting material. The reaction was considered to becomplete. The reaction mixture was filtered, and the aqueous phase wasseparated and discarded. The organic phase was washed 2×95 mL withwater, then filtered through a 18.7 g pad of flash grade silica. Thesilica pad was washed 1×100 mL with fresh methylene chloride. The crudecarbonate was concentrated by rotary evaporation. After chasing theresultant thick brown oil with 75 mL of heptane, the residue wascrystallized from 95 mL of heptane. The resultant slurry was cooled to 0to 5° C., held at temperature for NLT 1 hour, thinned by the addition ofan additional 25 mL of heptane, then filtered. The wetcake was washedwith 25 mL with fresh cold heptane, then dried in a vacuum dessicatorovernight.

[0204] The dried material weighed 11.09 g (68.0% yield). HPLC purity was98.3%.

Example 10 Preparation of 3-(3-Quinolyl)-2-Propen-1-ol t-Butyl Carbonate

[0205] To a 1-L three-neck round-bottom flask equipped with mechanicalstirrer, J-Kem temperature probe, transfer cannula, and dry nitrogenline was charged 3-(3-quinolyl)-2-propenoate (18.78 g, 88.07 mmol, 1.0equiv) and 280 mL (15 mL/g) of dry THF. The contents were mixed todissolve and then cooled to −50±5° C. A solution of DIBAL in toluene(102.02 g of 25 wt % solution; 25.5 g active DIBAL, 179.3 3 mmol, 2.03equiv) was slowly charged over 2 hours, and the temperature wasmaintained at NMT −45° C. during the addition. Once the addition wascomplete the reaction mixture was warmed to −30±5° C. An HPLC sample wastaken at T=3 hours, and revealed that the reaction was complete.

[0206] The reaction was quenched by the slow addition of 50 mL of coldtap water, maintaining a temperature of NMT −30° C. The reaction mixturewas then warmed to 0° C. and stirred at temperature for NLT 2 hours. Thecooling bath was removed and the reaction mixture was allowed to warm toroom temperature with stirring overnight.

[0207] The following morning the reaction mixture was filtered to removethe precipitated aluminum salts. The salts were washed with anadditional 2×100 mL of fresh THF. The combined organic phases werecooled to 0 to 5° C. then 20.0 g of BOC anhydride was added, followed by1.1 g of tetrabutylammonium hydrogen sulfate, and 55 mL of 25% aqueoussodium hydroxide. HPLC at T =4.74 hours revealed 8.8% remaining startingmaterial. An additional 6.0 g of BOC anhydride was charged, along with10 mL of 25% aqueous sodium hydroxide. The reaction mixture was thenstirred at room temperature overnight.

[0208] The following morning HPLC analysis revealed starting materialwas still present. Additional BOC anhydride (16.0 grams) and sodiumhydroxide solution (20 mL) was needed to push the reaction to completion(T=29.5 hours).

[0209] The crude reaction mixture was filtered to remove solids, and theremaining organic phase was washed 2×50 mL with water and 1×50 mL withbrine. The aqueous phases were then back extracted with 50 mL oftoluene. The combined organic phases were concentrated to a thick oil.After chasing the resultant thick brown oil with 75 mL of heptane, theresidue was crystallized from 75 mL of heptane. The resultant slurry wascooled to 0 to 5° C., held at temperature for NLT one hour, thinned bythe addition of an additional 25 mL of heptane, then filtered. Thewetcake was washed with 25 mL with fresh cold heptane, then dried in avacuum dessicator ovenight.

[0210] The dried material weighed 16.74 g (66.6% yield). HPLC purity was98.9%.

Example 11 Preparation of 3-(3-Quinolvl)-2-Propen-1-ol t-Butyl Carbonate

[0211] Step (1): Preparation of 3-(3′-quinolyl)-2-propenoic acid (Scheme4, Compound (12))

[0212] Methyl 3-(3′ quinolyl)-2-propenoate (25 g, 117 mmol) (Scheme 4,Compound (11)); see Example 8, Step (1) for preparation) and methanol(125 mL) were charge to a three-necked round-bottom flask equipped withan overhead stirrer. Sodium hydroxide (23.5 g, 588 mmol) was dissolvedin water (50 mL) and added to the suspension to provide a homogeneoussolution. The reaction was stirred for 1-3 hours prior to addingadditional water (250 mL). Concentrated hydrochloric acid was then addedin batches until the solution was slightly acidic (55-60 mL, 12 N). Thisresulted in the precipitation of a white solid. The solid was isolatedby filtration and washed with water and methanol. The white, crystallineproduct was then dried in a vacuum oven at ambient temperature. Isolatedyields ranged from 20 g, 86% to 22.2 g, 95%.

[0213] Step (2): Preparation of 3-(3-quinolyl)-2-propen-1-ol (Scheme 4,Compound (6))

[0214] 3-(3′-Quinolyl)-2-propenoic acid (2.5 g, 12.5 mmol) andtetrahydrofuran (50 mL) were charged to a round-bottom flask equippedwith a temperature probe and magnetic stirrer. The suspension was cooledto 0° C. and 4-methylmorpholine (1.93 g, 1.9 mmol) was added rapidlyfollowed by slow addition of isobutylchloroformate (1.93 g, 14 mmol)over 30 minutes maintaining an internal temperature less than 5° C. Themixture was then stirred at 0° C. for an additional hour and thenfiltered into water (7.5 mL) which was cooled to 0° C. The light yellowsolution was kept at 0° C. and the sodium borohydride (1 g, 26.5 mmol)was added in batches over 45 minutes to maintain a temperature below 5°C. Following addition, the reaction was stirred an additional 1.5 hoursat 0° C.

[0215] The reaction was quenched with slow addition 3 N HCl (40 mL) at0° C. The resulting orange-red solution was extracted with ethyl acetate(50 mL) to remove some impurities. The acidic aqueous layer, whichcontained the product, was neutralized with saturated sodium bicarbonatesolution and extracted with ethyl acetate (4×50 mL). The combine organicextracts were dried with magnesium sulfate and filtered though a plug ofsilica gel to remove some of the red color. The resulting light yellowliquid was concentrated to give the crude alcohol as an orange-red oil(1.87 g, 10.1 mmol, 81% yield, HPLC purity 90%).

[0216] Step (3): Preparation of 3-(3-quinolyl)-2-propen-1-ol t-butylCarbonate

[0217] The 3-(3-quinolyl)-2-propen-1-ol was treated in accordance withStep (3) of Example 1 to obtain the desired t-butyl carbonate.

Examples 12-16

[0218] Examples 12-16 relate to methods for preparing1-(3-quinolyl)-2-propen-1-ol t-butyl carbonate.

Example 12 Preparation of 1-(3-Quinolyl)-2-Propen-1-ol t-Butyl Carbonatevia 2-Iodo-3-Ouinoline Carboxaldehyde (Scheme 5, Compound (II))

[0219] Step (1): Preparation of 2-iodo-3-quinoline carboxaldehyde(Scheme 5, Compound (13))

[0220] To a dry three-necked round-bottom flask equipped with nitrogeninlet and overhead stirrer, reflux condenser was charged2-chloro-3-quinolinecarboxaldehyde (20 g, 104 mmol) and CH₃CN (200 ml)followed by sodium iodide (39 g, 260 mmol) and conc. HCl (cat, 4 ml) andthe solution was heated to reflux for 6 h. The reaction mixture wasevaporated to about ½ the volume, poured onto water (250 ml) andsaturated sodium carbonate (100 ml). The iodo derivative crystallisesout and it was filtered and dried under vacuum at 40° C. for 48 hrs.Yield =21 g (71%).

[0221] Step (2): Preparation of 1-(3-quinolyl)-2-propen-1-ol t-butylCarbonate

[0222] To a solution of 2-iodo-3-quinoline carboxaldehyde (3 g, 10.6mmol) in THF (25 ml) at −5° C., vinylmagnesium bromide (1 M solution,10.8 ml, 10.8 mmol) was added. It was stirred at that temperature untilthe starting material disappears, which takes about one hour.N-butyllithium (8.5 ml, 2.5 M soln, 21.2 mmol) was added and thesolution was stirred for another 25 min and then quenched with t-butanol(1.63 g, 22 mmol, only the C-2 anion is being quenched). Then a solutionof di-tert-butyl dicarbonate (2.54 g, 11.6 mmol) was added and thesolution was stirred for 2 h at −5° C. The reaction was then worked upwith MTBE (60 ml) and 10% ammonium chloride solution (25 ml). Theorganic layer washed again with saturated NaCl solution and it wasconcentrated to an orange oil which crystallised on standing at 0° C.overnight. It was used as such for alkylation experiments. Yield =2.8 g(92.7%)

Example 13 Preparation of 1-(3-Quinolyl)-2-Propen-1-ol t-Butyl Carbonatevia Condensation with Ethynylmagnesium Chloride (Scheme 5, Compound(II))

[0223] Step (1): Condensation of quinoline-3-carboxaldehyde withEthynylmagnesium Chloride (Scheme 5, Compound (II), wherein R⁸ is —C≡CRand R¹¹ is Hydrogen)

[0224] To a stirred slurry of quinoline-3-carboxaldehyde (5 g, 31.8mmol) in tetrahydrofuran (15 ml) at −150° C., was added ethynylmagnesiumchloride (66.8 ml, 33.4 mmol, 0.5 M in THF) at −10 to −15° C. A clearsolution which was formed after the addition was stirred at −15° C. for30 minutes. HPLC showed reaction was complete. This was transferred bycannula to a stirred solution of di-tert-butyl dicarbonate (7.84 g, 41.3mmol) in tetrahydrofuran (10 ml) at −10 to −15° C. The mixture waswarmed to 10° C. in one hour. HPLC showed complete disappearance of theGrignard adduct. The reaction mixture was cooled to −50° C., dilutedwith 50 ml of methyl t-butyl ether and quenched with a solution ofcitric acid (8 g) in water (45 g) at <10° C. After 30 minutes mixing,the organic layer was washed with 60 ml of saturated sodium bicarbonateand 2×30 ml water. The organic solution was filtered through a bed offilter aids, and the filtrate was concentrated under vacuum to an oil.The oil was azeotropically dried with 2×50 ml of ethyl acetate to givethe crude oil (10.4 g). Column chromatography (silica gel, 30:70EtOAc/hexane) gave pure fraction of the desired product (8.65 g) as avery viscous light yellow oil. Yield was 96.1%. MS(m/z) 284(M+H). H¹ NMR(ppm, CDCl₃): 9.08 (d, 1H), 8.35 (d, IH), 8.12 (dd, 1H), 7.87 (dd, 1H),7.75 (m, 1H), 7.58 (m, 1H), 7.47 (d, 1H), 2.82 (d, 1H), 1.50 (s, 9H).

[0225] Step (2): Preparation of 1-(3-quinolyl)-2-propen-1-ol t-butylcarbonate (Scheme 5, Compound (II) wherein R⁸ is —CH═CHR¹¹ and R¹¹ isHydrogen)

[0226] A solution of 1-(3-quinolyl)-2-propyn-1-ol t-butyl carbonate (1.5g, 5.3 mmol) in isopropanol (30 ml) was degassed and nitrogen purgedtwice. 5% palladium on calcium carbonate poisoned with lead (Lindlar'scatalyst, (0.11 g, 0.05 mmol) was added. The mixture was again evacuatedtwice, and a hydrogen balloon was placed over the flask with vigorousstirring at room temperature overnight. HPLC showed reaction wascomplete, and the catalyst was filtered off. The filtrate wasconcentrated under vacuum to give an oil (1.57 g). The oil was purifiedby column chromatography (silica gel, 30:70 EtOAc/hexane) to give thepure product (1.41 g). Yield was 93.3%. MS(m/z) 286(M+H)⁺. H¹ NMR (ppm,CDCl₃): 8.94 (d, 1H), 8.15 (d, 1H), 8.11 (d, 1H), 7.80 (dd, 1H), 7.70(m, 1H), 7.52 (m, 1H), 6.27 (s, 1H), 6.05-6.18 (m, 2H), 5.30-5.45 (m,2H), 1.50 (s, 9H).

Example 14 Preparation of 1-(3-Quinolyl)-2-Propen-1-ol t-Butyl Carbonatevia Condensation with Ethynylmagnesium Bromide (Scheme 5, Compound (II))

[0227] To a stirred solution of quinoline-3-carboxaldehyde (5 g, 31.8mmol) in tetrahydrofuran (15 ml) at −15° C. was added ethynylmagnesiumbromide (66.8 ml, 0.5M in THF) at −10 to −15° C. The reaction wascomplete after 50 minutes by HPLC. This solution was transferred to astirred solution of di-tert-butyl dicarbonate (7.84 g, 3 5.9 mmol) inTHF (10 ml) at −10 to −15 ° C. After the transfer, the mixture waswarmed to room temperature. Reaction was determined to be complete at 3hours by HPLC. The mixture was cooled back down to −50° C., diluted with50 ml of methyl t-butyl ether and quenched with a solution of citricacid (8 g) in water (45 ml) at <10° C. The organic layer was washed with60 ml of saturated sodium bicarbonate and 200 ml water. Afterfiltration, the organic layer was concentrated to dryness,azeotropically dried with 2×50 ml ethyl acetate to give a brown oil (9.5g). Column chromatography (silica gel, 30:70 EtOAc/hexane) gave pureproduct (8.45 g). Yield was 93.4%.

[0228] The product obtained from this reaction is identical to that fromethynylmagnesium chloride. The product can be reduced to provide the1-(3-quinolyl)-2-propen-1-ol t-butyl carbonate by methods described inExample 13, Step (2).

Example 15 Preparation of 1-(3-Quinolyl)-2-Propen-1-ol t-Butyl Carbonatevia Condensation with Vinylmagnesium Chloride (Scheme 5, Compound (II))

[0229] To a stirred solution of quinoline-3-carboxaldehyde (3 g, 19.1mmol) in tetrahydrofuran (15 ml) at −10° C., was added vinylmagnesiumchloride solution in THF (11.3 ml, 15 wt. %, d=0.975 g/mL) at −5 to −10°C. At the end of the addition, HPLC showed reaction was complete. Thisbrown solution was transferred by cannula to a stirred solution ofdi-tert-butyl dicarbonate (4.4 g, 22.9 mmol) in THF (10 ml) at −10 to-15° C. After the transfer, the reaction was warmed to 0-5° C. for 1hour. The mixture was cooled back down to −10° C., diluted with 60 ml ofmethyl t-butyl ether and quenched with a solution of citric acid (4.8 g,22.9 mmol) in water (27 ml) at <5° C. After 5 hours mixing, the organiclayer was separated, washed with 30 ml of 7% sodium bicarbonate. 2×30 mlwater, filtered and the filtrate was concentrated under vacuum to alight brown oil (5.5 g). Column chromatography (silica gel, 20:80EtOAc/hexane) of the crude product gave pure carbonate (4.3 g). Yieldwas 79.0%.

[0230] Spectral data of this material are consistent with that obtainedby reduction of the ethynyl carbonate.

Example 16 Preparation of 1-(3-Quinolyl)-2-Propen-1-ol t-Butyl Carbonatevia Condensation with Vinylmagnesium Bromide (Scheme 5, Compound (II))

[0231] A solution of quinoline-3-carboxaldehyde (2 g, 12.7 mmol) in THF(10 ml) was cooled to −20° C., and 1 M vinylmagnesium bromide (12.7 ml,12.7 mmol) was added at −15 to −20° C. At the end of the addition,reaction was complete. This brown solution was transferred to a solutionof di-tert-butyl dicarbonate (3.6 g, 16.5 mmol) in THF (10 ml) at −30°C. The solution was gradually warmed to room temperature and stirred for2 hours. The mixture was cooled back down to −50° C., and quenched witha solution of citric acid (3.2 g) in 18 g water at −5 to 5° C. After onehour stirring, the organic layer was washed with 20 ml of 7% sodiumbicarbonate and 2×20 ml water. The organic layer was concentrated todryness and chromatographed by silica gel column to give the pureproduct (2.1 g). Yield was 57.9%.

Examples 17-20

[0232] Examples 17-20 illustrate methods for preparing aquinoline-3-carboxaldehyde, which can be used as an intermediate in thesynthesis of carbonate or carbamate compounds of general formula (I),(II) or (III). The prepared quinoline-3-carboxaldehyde is treatedaccording to syntheses described in Schemes 5 and 7 as detailed by thedescription and Examples herein to provide the desired carbonate orcarbamate compounds.

Example 17 Preparation of Quinoline-3-Carboxaldehyde

[0233] Step 1: Preparation of 2-chloro-quinoline-3-carboxaldehydedimethylacetal (Scheme 6 Compound (16))

[0234] To a 250-mL three-necked round-bottom flask equipped withmechanical stirrer, temperature controller, heating mantle, refluxcondenser and dry nitrogen line was chargedquinoline-2-chloro-3-carboxaldehyde (11.7 g, 61.06 mmol) and 120 mL ofmethanol. The reaction was heated under reflux for one hour. Thereaction was monitored by thin layer chromatography (40:60 ethylacetate/heptane), which showed conversion to the acetal was completeafter one hour. The product solution was used directly fordehalogenation in Step 2.

[0235] Step 2: Preparation of quinoline-3-carboxaldehyde dimethylacetal(Scheme 6, Compound (17))

[0236] A solution of 2-chloro-quinoline-3-carboxaldehyde dimethylacetalwas charged to a second vessel containing 0.7 g of 10% Pd on carbon (50%wet) and potassium carbonate (12.5 g, 90.44 mmol). The reaction vesselwas evacuated then filled with hydrogen gas (3×) at 1 atmosphere. Aftercompletion of the reaction, the catalyst was removed by filtration andwashed with methanol. The solvent was removed by rotary evaporation. Theoily residue was dissolved in 120 mL of isopropyl acetate and washed 3times with 60 mL of water. The organic phase was then concentrated to anoil by rotary evaporation to afford the product as an oil (12.4 g,100%). MS: M/Z 204 (M+H⁺); ¹H NMR (CDCl₃, δ) 3.40 (s, 6H), 5.65 (broads, 1H), 7.55 (m, 1H), 7.73 (m, 1H), 7.86 (dd, 1 H), 8.13 (d, 1H), 8.25(d, 1H), 8.99 (d, 1H).

[0237] Step 3: Preparation of quinoline-3-carboxaldehyde (Compound (15))

[0238] To a 250-mL three-necked round-bottom flask equipped withmagnetic stirring, temperature controller, heating mantle, refluxcondenser and dry nitrogen line was charged 4.5 g of crude acetal, 30 mLof isopropanol, and 22 mL of 88% formic acid. This mixture was heatedunder reflux and monitored by thin layer chromatography (40:60 ethylacetate/heptane). After completion of the reaction, the mixture wasconcentrated by rotary evaporation. The residue was partitioned between50 mL portions of ethyl acetate and 5% sodium bicarbonate. Afterdiscarding the aqueous phase, the organic phase was washed 1×50 mL withwater. The organic phase was then concentrated to an oil by rotaryevaporation. The crude product was dissolved in hot heptane, filteredthrough celite to remove a small amount of oily residue, thenconcentrated to a light yellow solid by rotary evaporation (86%). MS:M/Z 158 (M+H⁺); ¹H NMR (CDCl₃, δ) 7.68 (m, 1H), 7.90 (m, 1H), 8.0 (dd,1H), 8.20 (dd, 1H), 8.64 (d, 1H), 9.48 (d, 1H), 10.26 (s, 1H).

Example 18 Preparation of Quinoline-3-Carboxaldehyde

[0239] Step (1): Quinoline-2-chloro-3-carboxaldehyde dimethylacetal(Scheme 6, Compound (16))

[0240] To a stirred solution of quinoline-2-chloro-3-carboxaldehyde (5g, 26 mmol) in methanol (150 ml) at room temperature, was bubbled inhydrochloric acid gas (1.7 g, 46.6 mmol). The solution was stirred atroom temperature for 25 minutes. Reaction was complete by HPLC. NaHCO₃(4.7 g, 56 mmol) was added to the reaction flask in portions and stirredfor 10 additional minutes. The solid precipitate was filtered off, thefiltrate was concentrated on a rotary evaporator to give an oil. The oilwas redissolved in ethyl acetate (75 ml), washed with H₂O (30 ml) andconcentrated to the product as an oil (6.2 g, 100%). MS: M/Z 238 (M+H⁺);¹H NMR (CDCl₃, δ) 3.45 (s, 6H), 5.72 (d, 1H), 7.58 (m, 1H), 7.75 (m,1H), 7.85 (dd, 1H), 8.25 (dd, 1H), 8.42 (s, 1H); ¹³C NMR (δ) 54, 100.4,126.8, 127.3, 128.1, 128.2, 129.2, 130.0, 137.2, 147.4, 149.3.

[0241] Step (2): Preparation of quinoline-3-carboxaldehyde

[0242] The quinoline-2-chloro-3-carboxaldehyde dimethylacetal from abovewas treated in accordance Steps (2) and (3) of Example 17 to obtainquinoline-3-carboxaldehyde.

Example 19 Preparation of Quinoline-3-Carboxaldehyde

[0243] Step (1): Preparation of quinoline-3-carboxaldehydedimethylacetal (Scheme 6, Compound (16))

[0244] A mixture of quinoline-2-chloro-3-carboxaldehyde acetal (0.8 g,3.4 mmol), triethylamine (0.69 g, 6.8 mmol) and 10% palladium on carbon(0.05 g, 50% wet) in methanol (15 ml) was nitrogen purged and evacuated.A hydrogen balloon was placed over the reaction flask, and the mixturewas vigorously stirred at room temperature for 15 h. HPLC showed nostarting material was left. The resulting mixture was degassed andnitrogen purged twice. The catalyst was filtered off and rinsed withmethanol. The filtrate and the rinse were combined, and concentrated toan oil. The oil was dissolved in ethyl acetate (25 ml) and washed withwater (20 ml). The ethyl acetate layer was concentrated to an oil whichwas purified by column chromatography (30:70 EtOAc/hexane) to give purequinoline-3-carboxaldehyde dimethylacetal (0.55 g, 80.4%).

[0245] Step (2): Preparation of quinoline-3-carboxaldehyde

[0246] The quinoline-3-carboxaldehyde dimethylacetal from above wastreated in accordance with Step (3) of Example 8 to obtainquinoline-3-carboxaldehyde.

Example 20 Preparation of Quinoline-3-Carboxaldehyde

[0247] Step (1): Preparation of quinoline-3-carboxaldehydedimethylacetal (Scheme 6, Compound (16))

[0248] Quinoline-2-chloro-3-carboxaldehyde (1.0 g, 5.2 mmol) wasdissolved in methanol (20 ml) and refluxed for 1.5 h. To this solutionwas added 10% palladium on carbon (100 mg) and ammonium formate (1.65 g,26 mmol) and refluxed for two hours to form quinoline-3-carboxaldehydedimethylacetal (>99%).

[0249] Step (2): Preparation of quinoline-3-carboxaldeh de Thequinoline-3-carboxaldehyde dimethylacetal from above was treated inaccordance with Step (3) of Example 8 to obtainquinoline-3-carboxaldehyde.

Examples 21-22

[0250] Examples 21-22 illustrate methods for preparing derivatives offormula (I) from quinoline-3-carboxaldehyde.

Example 21 Preparation of 3-(3-Quinolyl)-2-Propen-1-ol t-Butyl Carbonatevia Condensation of Quinoline-3-Carboxaldehyde with Ethyl Acetate(Scheme 7 Compound (II))

[0251] Step (1): Condensation of quinoline-3-carboxaldehyde with ethylacetate

[0252] To a 50-mL round-bottom flask equipped with magnetic stirring anda dry nitrogen line was added 1.1 g (7.0 mmol =1.0 equiv) ofquinoline-3-carboxaldehyde and 1 1.0 mL of ethyl acetate. This was mixedto dissolve and the resultant solution was cooled to 0-5° C. in anice/water bath.

[0253] To this solution was charged 1.03 g (8.4 mmol 1.2 equiv) ofpotassium t-butoxide in a single portion. Continue stirring the mixtureat 0-5° C. TLC at t=2 hr. revealed that the reaction was complete.Acetic acid (506 mg=8.4 mmol=1.2 equiv) was then charged to neutralizethe base. This mixture was then washed with 5% sodium bicarbonatesolution until the aqueous phase remained basic. The mixture was dilutedwith ethyl acetate as needed to assist in the washing. The organic phasewas then concentrated by rotary evaporation to yield 1.1 g of crudeproduct. The crude material can be recrystallized from 10% ethylacetate/heptane.

[0254] Step (2): Preparation of 3-(3-quinolyl)-2-propen-1-ol t-butylCarbonate

[0255] The ethyl 3-(3-quinolyl)-2-propenoate was treated in accordancewith Steps (1)-(3), Example 7 to obtain 3-(3-quinolyl)-2-propen-1-olt-butyl carbonate.

Example 22 Preparation of 3-(3-Quinolyl)-2-Propen-1-ol t-Butyl Carbonatevia Condensation of Quinoline-3-Carboxaldehyde

[0256] Step (1): Preparation of 3-(3-quinolyl)propenal (Scheme 7Compound (9))

[0257] To a 500-mL round-bottom flask, equipped with mechanical stirrer,dropping funnel and temperature bath was charged 30.9 g (0.2 mol)quinoline 3-carboxaldehyde and acetaldehyde (50 mL). The mixture wascooled to −10° C. and a solution of sodium hydroxide (500 mg) inmethanol (8 mL) was added dropwise keeping the temperature below 10° C.The mixture was stirred at 0° C. for 30 min. Acetic anhydride (50 mL)was added and the mixture was heated to 70° C. (methyl acetate formed inthe reaction was removed). After 1 hour, the mixture was cooled to 30°C. and 100 mL 3N HCI (50 mL conc. HCI in 100 mL water) was added. Themixture was heated to 80° C. for 45 min. and neutralized with 10% sodiumcarbonate solution. (The organic layer, containing product, was checkedby TLC, system isopropyl acetate, visualize under short UV). At the endof the reaction, the mixture was cooled to <30° C., diluted with 200 mLwater and it was washed with 2×150 mL isopropyl acetate. To the aqueouslayer was then added isopropyl acetate (500 mL) and the pH was broughtto >8 by neutralization with sodium carbonate. The organic layer wasseparated and concentrated to a small volume until the product starts tocrystallize. The mixture was stirred for 30 min. filtered and dried togive 18.5 g product as a light yellow solid. A second crop (5.4 g) wascollected by concentration of the mother liquor and filtration of thesolid product followed by washing with MTBE (25 mL). Total yield, 23.9 g(66%). The NMR of the product was consistent with the proposedstructure.

[0258] Step (2): Preparation of 3-(3-quinolyl)-2-propen-1-ol (Scheme 7.Compound (3))

[0259] A mixture of 3-(3-quinolyl)propenal (10 g, 54.6 mmol) in methanol(50 mL) was cooled to 0° C. and to this mixture, sodium borohydride(1.03 g, 27 mmol) was charged in small portions keeping the temperaturebelow 10° C. After the addition was complete, the mixture was stirred at23° C. for 90 min. until the reaction was complete as monitored by TLC(isopropyl acetate, visualize under uv). To the mixture, saturatedammonium chloride solution (20 mL) was added and the mixture was stirredfor one hour. The mixture was then concentrated under vacuum at 45° C.to remove methanol. The product was extracted in isopropyl acetate (150mL), and the solvent was evaporated under vacuum to dryness. The productwas triturated with MTBE (40 mL), filtered, washed with MTBE (10 mL) anddried to give 3-(3-quinolyl)-2-propen-1-ol (6.6g, 65.4%) as a lightyellow solid. The NMR of the product was consistent with the proposedstructure.

Examples 23-27

[0260] Examples 23-27 relate to methods for preparing a carbamatederivatives of the general formula (I). The 3-(3-quinolyl)-2-propyn-1-olderivatives can be used to obtain the propenyl carbamate derivatives ofthe general formula.

Example 23 Preparation of 3-(3-Ouinolyl)-2-Propyn-1-ol DicyclohexylCarbamate (Scheme 1, Compound (I))

[0261] To a dry three-necked round-bottom flask equipped with nitrogeninlet and overhead stirrer was charged 3-(3-quinolyl)-2-propyn-1-ol (1g, 5.4 mmol) in THF (10 ml) and the solution was cooled to 0° C.Potassium t-butoxide (0.67 g, 5.9 mmol) was then added followed bydicyclohexylcarbamoyl chloride (1.32 g, 5.4 mmol). The mixture wasstirred for 2 hours at 0° C. and then allowed to warm up to roomtemperature over a period of 6 hours by which time the reaction wasdetermined to be complete. The reaction mixture was worked up with MTBE(50 ml) and 10% NH₄Cl (25 ml) and the organic layers were concentratedto an oil. The purity compared to the standard was 94% and was used assuch. Yield 2 g (95%).

Example 24 Preparation of 3-(3-Quinolyl)-2-Propyn-1-ol DiphenylCarbamate (Scheme 1, Compound (I))

[0262] To a dry three-necked round-bottom flask equipped with nitrogeninlet and overhead stirrer was charged 3-(3-quinolyl)-2-propyn-1-ol (5g, 27 mmol) in THF (50 ml) and the solution was cooled to 0° C.Potassium t-butoxide (3.6 g, 32 mmol) was then added followed bydiphenylcarbamoyl chloride (6.9 g, 29.7 mmol). The mixture was stirredfor 2 hours at 0° C. and then allowed to warm up to room temperatureover a period of 6 hours by which time the reaction was determined to becomplete. The reaction mixture was worked up with MTBE (100 ml) and 10%NH₄Cl (50 ml) and was concentrated to ¼ the volume. Heptane (75 ml) wasadded and the product was crystallised out. Yield=8.3 g (80%).

Example 25 Preparation of 3-(3-Quinolyl)-2-Propyn-1-ol DiisopropylCarbamate (Scheme 1, Compound (I))

[0263] To a dry three-necked round-bottom flask equipped with nitrogeninlet and overhead stirrer was charged 3-(3-quinolyl)-2-propyn-1-ol (2g, 10.8 mmol) (Scheme 1, Compound (3)) in THF (20 ml) and the solutionwas cooled to 0° C. Potassium t-butoxide (1.34 g, 11.9 mmol) was thenadded followed by diisopropylcarbamoyl chloride (1.65 g, 11.9 mmol). Themixture was stirred for 2 h at 0° C. and then allowed to warm up to roomtemperature over a period of 6 hours by which time the reaction wasdetermined to be complete. The reaction mixture was worked up with MTBE(50 ml) and 10% NH₄Cl (25 ml) and was concentrated to an orange oil.Yield=3.3 g(100%)

Example 26 Preparation of 3-(3-Quinolyl)-2-Propyn-1-ol MorpholineCarbamate (Scheme 1, Compound (I))

[0264] To a dry three-necked round-bottom flask equipped with nitrogeninlet and overhead stirrer was charged 3-(3-quinolyl)-2-propyn-1-ol (2g, 10.8 mmol) (Scheme 1, Compound (3)) in THF (20 ml) and the solutionwas cooled to 0° C. Potassium t-butoxide (1.34 g, 11.9 mmol) was thenadded followed by morpholine acid chloride (1.95 g, 13 mmol). Themixture was stirred for 2 hours at 0° C. and then allowed to warm up toroom temperature over a period of 6 hours by which time the reaction wasdetermined to be complete. The reaction mixture was worked up with MTBE(50 ml) and 10% NH₄Cl (25 ml), concentrated to an orange oil, andpurified by column chromatography using heptane and ethyl acetate aseluant. A total of 1.4 g was obtained as pure fraction (100%). Yield=1.4g (44%)

Example 27 Preparation of 3-(3-Quinolyl)-2-Propen-1-ol ImidazoleCarbamate (Scheme 1, Compound (I))

[0265] To a dry three-necked round-bottom flask equipped with nitrogeninlet and overhead stirrer was charged 3-(3-quinolyl)-2-propen-1-ol (5g, 27 mmol) (Scheme 1, Compound (3)) in CH₂Cl₂ (50 ml) andcarbonyldiimidazole (4.82 g, 29.7 mmol) was added and the mixture wasstirred at room temperature for 8 h. The reaction mixture was worked upby quenching with 10% NH₄Cl (25 ml) and concentrated ¼ the volume.Heptane (50 ml) was added and the product crystallised out. Yield=7.2 g(95.5%)

Example 28

[0266] Examples 28 illustrates a method for preparing an allyl carbonatecompound of the general formula (I).

Example 28 Preparation of Allyl t-Butyl Carbonate

[0267] A 3-L three-necked round-bottom flask equipped with mechanicalstirring, a nitrogen inlet adapter and a pressure equalizing additionfunnel was charged with allyl alcohol (149.5 g, 2.57 mol), di-tert-butyldicarbonate (510 g, 2.34 mol), and CH₂Cl₂ (1200 mL) and cooled to 0° C.A 0° C. solution of 30% NaOH (aq.) (1000 mL, 7.5 mol, 3.2 equiv) wasadded dropwise to the rapidly stirring solution at such a rate that theinternal temperature did not rise above 20° C. (about 1 hour). Thereaction mixture was stirred at 20° C. for 2 hours prior to workup.

[0268] The crude reaction mixture was partitioned between 1 L water and500 mL CH₂Cl₂.The organic layer was separated, washed with 1 L water and1 L saturated NaCI solution, dried over MgSO₄, filtered and reduced todryness in-vacuo, to afford about 300g of a yellow oil. The crudeproduct was purified by fractional distillation, b.p. 96° C. at 70 mmHg,affording the product as a colorless oil, 250.3 g (68%). The product hada b.p. of 96° C. at 70 mmHg. ¹H NMR (CDCl₃, 300 MHz): d 5.95 (m, 1H),5.3 (appar quartet of quartets, 2H), 4.55 (appar doublet of triplets,2H), 1.49 (s, 9H). ¹³C NMR (CDCl₃, 75 MHz): d 153.1, 131.9, 118.3, 81.9,67.4, 27.6. MS (NH₃, CI): 176 (M+NH₄)⁺. Anal Calc'd for C₈H₁₄O₃: C,60.73; H, 8.92. Found: C, 60.95; H, 8.96.

What is claimed is:
 1. A process of preparing a compound of the formulaR¹—CH═CHCH₂OC(O)—X—R²  (I), wherein R¹ is independently selected fromhydrogen and quinolyl optionally substituted with one or more of: (i)alkyl, (ii) alkoxy, (iii) aryl, (iv) nitro, and (v) halo; R² isC₁-C₁₀-alkyl; X is —O— or —NR³; R³ is hydrogen, C₁-C₆-alkyl or aryl; orR² and R³ taken together form an aromatic or non-aromatic ring,comprising the steps of: (a) preparing an intermediate selected from:(i) R¹—C≡CCH₂OR⁴, wherein R⁴ is hydrogen or a hydroxy protecting group;(ii) R¹—-CH═CHC(O)OR⁵, wherein R⁵ is C₁ to C₆ lower alkyl; (iii)R¹—CH═CHCH(OR⁶)(OR⁷), wherein R⁶ and R⁷ are independently C₁ to C₆alkyl; (iv) R¹—CH═CHC(O)OH; (v) R¹—CH═CHCHO; and (vi)R¹—C≡C—CH₂—OC(O)—X—R²; (b) reducing or deprotecting an intermediateobtained in step (a); and (c) optionally coupling the compound obtainedfrom step (b) with an acylating reagent.
 2. The process according toclaim 1, wherein R² is isopropyl or t-butyl.
 3. The process according toclaim 1, wherein the intermediate of the formula R¹—C≡CCH₂OR⁴ isobtained by a process comprising the steps of reacting a haloquinolinewith propargyl alcohol or a substituted propargyl alcohol of the formulaHC≡CCH₂OR⁴, wherein R⁴ is hydrogen or a hydroxy protecting group.
 4. Theprocess according to claim 1, wherein the intermediate of the formulaR¹—CH═CHC(O)OR⁵, is obtained by reacting a vinyl ester of the formulaCH₂═CHC(O)OR⁵, wherein R⁵ is Cl to C₆ alkyl, with a haloquinoline. 5.The process according to claim 1, wherein the intermediate of theformula R¹—CH═CHC(O)OR⁵, is obtained by reacting an ester of the formulaCH₃C(O)OR⁵, wherein R⁵ is C₁ to C₆ alkyl, with a quinolinecarboxaldehyde.
 6. The process according to claim 1, wherein theintermediate of the formula R¹—CH═CHCH(OR⁶)(OR⁷), is obtained byreacting an acetal of the formula CH₂═CHCH(OR⁶)(OR⁷), wherein R⁶ and R⁷are independently C₁ to C₆ alkyl, with haloquinoline.
 7. The processaccording to claim 1, wherein the intermediate of the formulaR¹—CH═CHC(O)OH is obtained by hydrolyzing a compound of the formulaR¹—CH═CHC(O)OR⁵.
 8. The process according to claim 1, wherein theintermediate of the formula R¹—CH═CHCHO is obtained by reducing theintermediate of formula R¹—CH═CHCH(OR⁶)(OR⁷).
 9. The process accordingto claim 1, wherein the intermediate of the formula R¹—CH═CHCHO isobtained via condensation of acetaldehyde with quinoline carboxaldehyde.10. The process according to claim 1, wherein the intermediaterepresented by the formula R¹—C≡CCH₂OR⁴ or R¹—C≡C—CH₂—OC(O)—X—R²obtained from step (a) is reduced by methods of catalyticsemi-hydrogenation.
 11. The process according to claim 10, wherein theintermediate is treated with hydrogen gas and a metal catalyst selectedfrom palladium and platinum catalysts.
 12. The process according toclaim 10, wherein the intermediate is treated with an aluminum hydridereagent and a metal catalyst selected from palladium and platinumcatalysts.
 13. The process according to claim 1, wherein theintermediate of the formula R¹—CH═CHC(O)OR⁵ is reduced with an aluminumhydride reagent.
 14. The process according to claim 1, wherein theintermediate of the formula R¹—CH═CHCHO or R¹—CH═CHC(O)OH obtained fromstep (a) is reduced using a boron reducing agent or an aluminum hydridereagent.
 15. The process according to claim 14, wherein the boronreducing agent is selected from the group consisting of a borane complexreagent or a borohydride reagent.
 16. The process according to claim 15,wherein the borane complex reagent is selected from borane-dimethylsulfide, borane-tetrahydrofuran complex, borane-pyridine complex,borane-morpholine, borane-trimethylamine complex, borane t-butylamine,borane-N,N-diisopropylethylamine, borane dimethylamine,4-(borane-dimethylamino)pyridine, borane-4-ethylmorpholine, andborane-4-methylmorpholine.
 17. The process according to claim 15,wherein the borohydride reagent is selected from borane, borane-methylsulfide, borane-methylsulfide 9-borabicyclononane, lithium borohydride,sodium borohydride, lithium borohydride, and potassium borohydride. 18.The process according to claim 12, 13 or 14 wherein the aluminum hydridereagent is selected from the group consisting of lithium aluminiumhydride alone or with AlCl₃, diisobutyl aluminum hydride, and sodiumbis(2-methoxyethoxy)aluminum hydride in toluene.
 19. The processaccording to claim 1, wherein the compound of the formulaR¹—C≡CCH₂OC(O)—X—R², is obtained by coupling an intermediate of theformula R¹—C≡CCH₂OR⁴ with an acylating reagent.
 20. A process ofpreparing a compound of the formula:

X is —O— or —NR³—; R¹ is independently selected from hydrogen andquinolyl optionally substituted with one or more substituents selectedfrom: (i) alkyl, (ii) alkoxy, (iii) aryl, (iv) nitro, and (v) halo; R²is C₁-C₁₀-alkyl; R³ is hydrogen or C₁-C₆-alkyl; or R² and R³ takentogether form an aromatic or non-aromatic ring; and R⁸ is selected fromthe group consisting of: (i) —CH═CH—R¹¹, wherein R¹¹ is hydrogen oralkyl; and (ii) —C≡CR¹¹; comprising the steps of: (a) reacting acompound of the formula:

wherein X¹ is a halide, with an organometallic compound of the formulaR⁸—M or R⁸—M—X¹, wherein R⁸ and X¹ are as defined above and M is metal,and (b) optionally hydrogenating the compound obtained in step (a),wherein R⁸ is alkynyl or substituted alkynyl, to afford thecorresponding compound wherein R8 is alkenyl or substituted alkenyl. 21.The process according to claim 20, wherein the metal is magnesium orlithium.
 22. The process according to claim 20, comprising the steps ofreacting a compound of the formula:

wherein X¹ is a halide, with a magnesium halide compound and an alkyllithium compound in an alcoholic solvent.
 23. The process of preparing acompound according to claim 20, wherein the quinoline carboxaldehyde isobtained by the process comprising the steps of: (a) reacting a2-halo-quinoline-3-carboxaldehyde having a formula:

wherein X¹ is a halide, to a 2-halo-quinoline-3-carboxaldehyde acetalhaving a formula:

wherein, X¹ is a halide and R⁹ and R¹⁰ are each independently C₁ to C₆lower alkyl, by reacting with an alcohol of the formula R⁹—OH, whereinR⁹ is C₁ to C₆ lower alkyl, or with an orthoformate of the formulaHO(OR¹⁰)₃, wherein R¹⁰ is C₁ to C₃ lower alkyl; (b) dehalogenating the2-halo-quinoline-3-carboxaldehyde acetal to form aquinoline-3-carboxaldehyde acetal having a formula:

(c) hydrolyzing the quinoline-3-carboxaldehyde acetal.
 24. The processaccording to claim 20, comprising the steps of: (a) reacting quinolinecarboxaldehyde with an acetaldehyde; (b) reducing the compound obtainedin step (a); and (c) coupling the compound obtained in step (b) with anacylating reagent.
 25. A compound of selected from: (a) R¹—CH═CHC(O)OR⁵,wherein R¹ is independently selected from hydrogen and quinolyloptionally substituted with one or substituent selected from (i) alkyl,(ii) alkoxy, (iii) aryl, (iv) nitro, and (v) halo; and R⁵ is C₁ to C₆lower alkyl; (b) R¹—CH═CHCH(OR⁶)(OR⁷), wherein R⁶ and R⁷ areindependently C₁ to C₆ alkyl; (c) R¹—CH═CHC(O)OH; (d) R¹CH═CHCHO; and(e) R¹—C≡C—CH₂—OC(O)—X—R²; wherein R² is C₁-C₁₀-alkyl; X is —O— or —NR³;and R³ is hydrogen, C₁-C₆-alkyl or aryl; or R² and R³ taken togetherform an aromatic or non-aromatic ring; and (f) R¹—CH═CHCH₂OH.
 26. Aprocess for preparing a compound of formula R¹—CH═CHCH₂OC(O)—X—R²  (I),X is —O— or —NR³—; R¹ is independently selected from hydrogen andquinolyl optionally substituted with one or more substituents selectedfrom: (i) alkyl, (ii) alkoxy, (iii) aryl, (iv) nitro, and (v) halo; R²is C₁-C₁₀-alkyl; R³ is hydrogen or C₁-C₆-alkyl; or R² and R³ takentogether form an aromatic or non-aromatic ring; comprising the steps of:(a) preparing a compound of the formula R¹—CH═CHCH₂OR⁴, wherein R⁴ ishydrogen or a hydroxy protecting group; (b) optionally deprotecting thecompound obtained in step (a); and (c) reacting a compound of theformula R¹—CH═CHCH₂OH with an acylating agent.
 27. A process forpreparing a compound of formula R¹—CH═CHCH₂OC(O)—X—R²  (I), X is —O— or—NR³—; R¹ is independently selected from hydrogen and quinolyloptionally substituted with one or more substituents selected from: (i)alkyl, (ii) alkoxy, (iii) aryl, (iv) nitro, and (v) halo; R² isC₁-C₁₀-alkyl; R³ is hydrogen or C₁-C₆-alkyl; or R² and R³ taken togetherform an aromatic or non-aromatic ring; comprising the steps of: (a)preparing a compound of the formula R¹—C≡C—CH₂—OC(O)—X—R²; and (b)hydrogenating the compound obtained in step (a).
 28. The processaccording to claim 26 or 27, wherein the acylating reagent isdi-tert-butyl dicarbonate.
 29. A compound having the formula

X is —O— or —NR³—; R¹ is independently selected from hydrogen andquinolyl optionally substituted with one or more substituents selectedfrom: (i) alkyl, (ii) alkoxy, (iii) aryl, (iv) nitro, and (v) halo; R²is C₁-C₁₀-alkyl; R³ is hydrogen or C₁-C₆-alkyl; or R² and R³ takentogether form an aromatic or non-aromatic ring; and R⁸ is selected fromthe group consisting of: (i) —CH═CH—R¹¹, wherein R¹¹ is hydrogen oralkyl, and; (ii) —C≡CR¹¹.